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fnins-13-01262 November 18, 2019 Time: 13:40 # 1
REVIEW
published: 20 November 2019
doi: 10.3389/fnins.2019.01262
Edited by:
Klaus H. Hoffmann,
University of Bayreuth, Germany
Reviewed by:
Liliane Schoofs,
KU Leuven, Belgium
Geoffrey Coast,
Birkbeck, University of London,
United Kingdom
Gáspár Jékely,
University of Exeter, United Kingdom
*Correspondence:
Dick R. Nässel
dnassel@zoologi.su.se
†ORCID:
Dick R. Nässel
orcid.org/0000-0002-1147-7766
Meet Zandawala
orcid.org/0000-0001-6498-2208
Honoo Satake
orcid.org/0000-0003-1165-3624
Specialty section:
This article was submitted to
Neuroendocrine Science,
a section of the journal
Frontiers in Neuroscience
Received: 27 September 2019
Accepted: 06 November 2019
Published: 20 November 2019
Citation:
Nässel DR, Zandawala M,
Kawada T and Satake H (2019)
Tachykinins: Neuropeptides That Are
Ancient, Diverse, Widespread
and Functionally Pleiotropic.
Front. Neurosci. 13:1262.
doi: 10.3389/fnins.2019.01262
Tachykinins: Neuropeptides That Are
Ancient, Diverse, Widespread and
Functionally Pleiotropic
Dick R. Nässel1*†, Meet Zandawala2†, Tsuyoshi Kawada3and Honoo Satake3†
1Department of Zoology, Stockholm University, Stockholm, Sweden, 2Department of Neuroscience, Brown University,
Providence, RI, United States, 3Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
Tachykinins (TKs) are ancient neuropeptides present throughout the bilaterians and
are, with some exceptions, characterized by a conserved FX1GX2Ramide carboxy
terminus among protostomes and FXGLMamide in deuterostomes. The best-known
TK is the vertebrate substance P, which in mammals, together with other TKs, has
been implicated in health and disease with important roles in pain, inflammation,
cancer, depressive disorder, immune system, gut function, hematopoiesis, sensory
processing, and hormone regulation. The invertebrate TKs are also known to have
multiple functions in the central nervous system and intestine and these have been
investigated in more detail in the fly Drosophila and some other arthropods. Here, we
review the protostome and deuterostome organization and evolution of TK precursors,
peptides and their receptors, as well as their functions, which appear to be partly
conserved across Bilateria. We also outline the distribution of TKs in the brains of
representative organisms. In Drosophila, recent studies have revealed roles of TKs in
early olfactory processing, neuromodulation in circuits controlling locomotion and food
search, nociception, aggression, metabolic stress, and hormone release. TK signaling
also regulates lipid metabolism in the Drosophila intestine. In crustaceans, TK is an
important neuromodulator in rhythm-generating motor circuits in the stomatogastric
nervous system and a presynaptic modulator of photoreceptor cells. Several additional
functional roles of invertebrate TKs can be inferred from their distribution in various brain
circuits. In addition, there are a few interesting cases where invertebrate TKs are injected
into prey animals as vasodilators from salivary glands or paralyzing agents from venom
glands. In these cases, the peptides are produced in the glands of the predator with
sequences mimicking the prey TKs. Lastly, the TK-signaling system appears to have
duplicated in Panarthropoda (comprising arthropods, onychophores, and tardigrades)
to give rise to a novel type of peptides, natalisins, with a distinct receptor. The
distribution and functions of natalisins are distinct from the TKs. In general, it appears
that TKs are widely distributed and act in circuits at short range as neuromodulators
or cotransmitters.
Keywords: substance P, neurokinin, neurokinin receptor, natalisin, G protein-coupled receptor, co-transmission,
neuropeptide evolution, tachykinin-related peptide
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Nässel et al. Tachykinins: Ancient Multifunctional Neuropeptides
INTRODUCTION
Substance P, the prototypic tachykinin (TK), was the first
neuropeptide ever to be isolated from brain tissue already in 1931
(Von Euler and Gaddum, 1931). For a long time it was the sole
brain neuropeptide known, and was joined only in the 1950s by
the pituitary peptides, oxytocin and vasopressin (Turner et al.,
1951;Du Vigneaud et al., 1953;Du Vigneaud, 1955). Today, the
number of neuropeptides identified in the animal kingdom is
huge and hard to overview [see (Jekely, 2013;Mirabeau and Joly,
2013;Nässel and Zandawala, 2019)]. Also, the number of TK
family members has grown immensely over the years, and we
know now that there often are several structural and functional
representatives in each species.
Already from the outset it was recognized that substance P
is produced both in the brain and the intestine (Von Euler and
Gaddum, 1931;Hökfelt et al., 2001). Today, it is clear that TKs are
utilized by neurons in the CNS, by neurons and enteroendocrine
cells associated with the intestine (Otsuka and Yoshioka, 1993;
Nässel, 1999;Hökfelt et al., 2001;Satake et al., 2013;Steinhoff
et al., 2014), as well as by other cells in mammals such as
hematopoietic cells (Zhang et al., 2000;Morteau et al., 2001),
endothelial cells, Leydig cells and immune cells [see (Almeida
et al., 2004)]. Thus, they are widespread and pleiotropic, and are
not only neuropeptides, but also produced by other cell types.
Although the first TK was identified in 1931, it was not until
1971 that substance P was purified and sequenced from 20 kg
bovine hypothalamus (Chang et al., 1971), and subsequently
synthesized (Tregear et al., 1971). This enabled production of
antisera and their application in radioimmunoassay (Powell
et al., 1973) and immunocytochemistry (Hökfelt et al., 1975)
to localize substance P and demonstrate its release. Thereafter,
important experimental work ensued, including development of
TK agonists and antagonists [see (Otsuka and Yoshioka, 1993;
Hökfelt et al., 2001)], identification of TK receptors [see (Masu
et al., 1987;Nakanishi, 1991)], developing genetic approaches and
discovering important roles in health and disease [see (Otsuka
and Yoshioka, 1993;Hökfelt et al., 2001;Onaga, 2014;Steinhoff
et al., 2014)]. The discovery of the roles of substance P and other
TKs in pain, inflammation, cancer, depressive disorder, immune
function, gut function, hematopoiesis, sensory processing and
hormone regulation [see (Hökfelt et al., 2001;Onaga, 2014;
Steinhoff et al., 2014;Zieglgänsberger, 2019)] has lead to extensive
research into the pharmacology and molecular biology of this
signaling system as a therapeutic target [see (Steinhoff et al.,
2014)], resulting in a huge number of publications annually.
However, it is hard to find recent comprehensive reviews on TKs
that cover distribution and functions.
Tachykinins have also been explored outside mammals and
other vertebrates. The first TK to be identified in an invertebrate
was eledoisin, isolated from salivary glands of the cephalopod
Eledone moschata (Erspamer and Anastasi, 1962). Eledoisin was
actually the first TK to be sequenced, but since the sequence
of substance P was not yet known, the structural relationship
was realized only later. The authors, however, recognized
that the action of eledoisin on mammalian smooth muscle is
similar to that of substance P (Erspamer and Anastasi, 1962;
Erspamer and Erspamer, 1962). Many years later, four TKs were
isolated from the brain and retrocerebral glands of the locust
Locusta migratoria (Schoofs et al., 1990a,b). Today, multiple TKs
(more than 350 sequences) have been identified from over 50
insect species [see the DINeR database1(Yeoh et al., 2017)],
and numerous ones from other invertebrates and protochordates
[see e.g., Kawada et al. (2010),Veenstra (2010, 2011, 2016),
Conzelmann et al. (2013),Palamiuc et al. (2017),Zandawala et al.
(2017),Dubos et al. (2018),Koziol (2018) and Figure 1 and
Supplementary Table S1]. Also in invertebrates, the common
TKs are produced by neurons of the CNS and by endocrine
cells of the intestine, but the presence of invertebrate TKs in
other cell types has not been reported thus far. Functional
analysis has revealed that invertebrate TKs are also pleiotropic.
Moreover, recent genetic work in Drosophila, suggests that many
TK functions are conserved over evolution.
In this review, we first comment on TK terminology in
invertebrates since at present it may seem somewhat complex
and confusing. Furthermore, we discuss the evolution of genes
encoding TK precursors and receptors as well as outline TK
signaling systems in various phyla across the animal kingdom.
Next, we discuss the distribution of TKs and functions of TK
signaling systems; here, we are more comprehensive in dealing
with invertebrates since vertebrate TK literature is very extensive.
Furthermore, we highlight the functions of TK-signaling that are
conserved across different animal phyla. Of note, TKs generally
appear to signal over a relatively short range within defined
neuronal circuits as neuromodulators or cotransmitters. Only
a few examples of intestinal TKs acting as local circulating
hormones are available. We also discuss a sister group of the TKs,
the natalisins, that seems to have arisen by a gene duplication
in the Panarthropoda (comprising arthropods, onychophores,
and tardigrades) lineage and appears restricted to this group.
The natalisins and their receptors constitute a distinct signaling
system that has not been investigated in detail thus far.
STRUCTURE OF TACHYKININ PEPTIDES
AND ORGANIZATION OF GENES
ENCODING THEIR PRECURSORS
We start this section with a commentary on TK terminology and
continue with describing TK precursors, peptides and receptors
in mammals where knowledge is the largest and then move on
with other vertebrates and last invertebrates.
A Note on Major Types of Tachykinins
and Terminology
Substance P (RPKPQQFFGLMamide), and other mammalian
TKs, are characterized by an FXGLMamide carboxy terminus,
and these peptides act on either of three TK receptors (GPCRs;
NK1R – NK3R) (Otsuka and Yoshioka, 1993;Onaga, 2014;
Steinhoff et al., 2014). The first invertebrate neuropeptides
referred to as TKs (locustatachykinin I-IV; LomTK I-IV),
1http://www.neurostresspep.eu/diner/insectneuropeptides
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FIGURE 1 | Sequence alignments of (A) tachykinin and (B) natalisin peptides
from select species. Note that C-terminal amidation is not shown; it is
represented by the amidation signal G. Conserved residues are highlighted in
black (identical) or gray (similar). Species belonging to the same phyla have
been highlighted with the same color. Species names are as follows: Homsa
(Homo sapiens), Danre (Danio rerio), Cioin (Ciona intestinalis), Astru (Asterias
rubens), Capte (Capitella teleta), Ureun (Urechis unicinctus), Cragi
(Crassostrea gigas), Octvu (Octopus vulgaris), Caeel (Caenorhabditis elegans),
Hypdu (Hypsibius dujardini), Tetur (Tetranychus urticae), Dappu (Daphnia
pulex), Trica (Tribolium castaneum), Bommo (Bombyx mori), Anoga
(Anopheles gambiae), Varde (Varroa destructor), Bacdo (Bactrocera dorsalis),
Drome (Drosophila melanogaster) and Nemve (Nematostella vectensis). Note
that the A. rubens, C. elegans and N. vectensis peptides are unlikely to be TKs
as they deviate substantially from the canonical TK sequences (see also text).
were isolated from the brain and retrocerebral complex of
locusts, and have a different carboxy terminus, FX1GX2Ramide
(Schoofs et al., 1990a,b). This sequence is shared by many other
invertebrate TKs and only one type of insect TK receptor is
known so far (Nässel, 1999;Van Loy et al., 2010;Satake et al.,
2013). The structural difference in the active core of the two
groups of TK peptides renders the FX1GX2Ramides inactive
on the vertebrate-type TK receptors and conversely, vertebrate
TKs do not activate invertebrate receptors (Satake et al.,
2013). Thus, these authors suggested that the FX1GX2Ramides
should be designated tachykinin-related peptides (TKRPs) to
distinguish them from vertebrate TKs with FXGLMamide. In
the literature, the individual TKs and TKRPs have been given
many different names. In invertebrates, these commonly include
a prefix indicating the species of origin (e.g., LomTK in Locusta
migratoria) and then numbers if multiple peptide paracopies
(isoforms) exist on the same precursor (LomTK-I, LomTK-II etc).
To further complicate the terminology of TKs, there are
peptides with an FXGLMamide carboxy terminus produced
by salivary glands of mosquitos, sialokinins (Champagne and
Ribeiro, 1994) and in cephalopods, eledoisin and octopus-
tachykinin (Erspamer and Anastasi, 1962;Kanda et al., 2003;
Satake et al., 2003) (Figure 2 and Supplementary Table S2).
These TKs are delivered to prey and meant to act on exogenous
receptors, not within the “sender animal” (predator). The
peptides of this kind were referred to as invertebrate TKs
(Inv-TKs) (Satake et al., 2003), to distinguish them from
TKRPs. Similarly, exocrine glands in amphibian skin produce
FXGLMamide-type TKs that have been given different exotic
names [see (Lazarus and Attila, 1993)]. A recent finding adds
to the TK complexity; in the parasitoid Jewel wasp (Nasonia
vitripennis), the toxin glands produce a precursor encoding
multiple FQGMRamide containing peptides (Arvidson et al.,
2019). The wasp injects the toxin that contains FQGMRamide
peptide and other components into the cockroach brain to
paralyze the host by acting on the cockroach TK receptor in
circuits of the central complex. In summary, TKs for exogenous
use are produced to act on receptors of target animals and the
salivary gland ones deviate structurally from native TKs. We will
discuss these in more detail later. In the present review, we use
the names originally given to the different TKs when relevant
(see Supplementary Tables 1,2), but for the sake of simplicity
we will henceforth use the term TKs for all FXGLMamide and
FX1GX2Ramides when we discuss the peptides in general.
A related, but distinct, invertebrate peptide signaling system
is constituted by the natalisins (NTL) and their receptors (Jiang
et al., 2013). These will be discussed separately. Also, note that
especially in early papers (but also some more recent ones) a
family of neuropeptides designated leucokinins (LKs) has been
considered related to TKs [see e.g., Holman et al. (1986),Nässel
and Lundquist (1991),Al-Anzi et al. (2010)]. The LKs have an
FXSWGamide carboxy terminus, and analysis based on precursor
structure (and receptors) show that they are not homologous to
TKs (Jekely, 2013;Mirabeau and Joly, 2013).
TKs and Their Receptors in Mammals
In mammals, including humans, there are three genes
encoding precursors of tachykinins: preprotachykinin A
(PPTA), preprotachykinin B (PPTB) and preprotachykinin
C (PPTC), also known as Tac1, Tac3, and Tac4, respectively
[see (Onaga, 2014;Steinhoff et al., 2014)]. These genes arose
through two rounds of genome duplications in the vertebrate
lineage followed by subsequent gene losses and diversification
(Elphick et al., 2018). The Tac1 precursor gives rise to Substance
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FIGURE 2 | Tachykinins produced by glands utilized on prey animals. (A) Sequences of TKs produced by salivary- or venom glands of cephalopods (O. vulgaris and
E. moschata) a wasp (A. compressa) and a mosquito (A. aegypti) compared to the endogenous TKs and TKs of prey animals (shown as SeqLogos). We use the
zebrafish D. rerio as an example for the possible cephalopod prey1. The endogenous TK of E. moschata is not known; that of O. vulgaris is shown instead2. Only
one sequence is shown. (B) Scheme of organization of tachykinin precursors and a natalisin precursor of A. aegypti. The salivary gland TK is designated sialokinin-I.
Red boxes represent tachykinins, and yellow boxes indicate natalisins. In addition, signal peptides are indicated by blue boxes. Bars indicate tachykinins (TK-2 and
TK-4) that are part of multiple exons.
P (SP), Neurokinin A (NKA), Neuropeptide K (NPK), and
neuropeptide γ(NPγ), Tac3 to Neurokinin B (NKB), and Tac4
to Hemokinin (HK), Endokinin-A (EKA) and Endokinin-B
(EKB). Thus, there are nine different TKs in mice, rats and
humans. The sequences of the Tac1 and Tac3 derived TKs
are conserved in humans, mouse and rat, whereas the ones
encoded on Tac4 differ between species (Steinhoff et al., 2014).
The Tac4 encodes another two endokinins (EKC and EKD)
that are not TKs (Steinhoff et al., 2014). The organization of
mammalian TK precursors is shown in Figure 3 and their
sequences in Table 1. For comparison, TK precursors in
other representative animals are shown in Figures 4,5, and a
cladogram with TK signaling components found in Figure 6.
It is also worth noting that the Tac1 and Tac4 genes each
give rise to 4 splice variants, α,β,γ, and δ(Onaga, 2014;
Steinhoff et al., 2014). The TKs have differential affinity for three
different TK receptors, NK1R - NK3R (or TAC1R - TAC3R)
(Nakanishi, 1991;Onaga, 2014;Steinhoff et al., 2014) as shown
in Table 1; the ligand selectivity is as follows: SP >NKA >NKB
for NK1R, NKA >NKB >SP for NK2R, and NKB >NKA >SP
for NK3R (Satake et al., 2013;Steinhoff et al., 2014). HK and
EKs exhibit the highest affinity to NK1R (Satake et al., 2013;
Steinhoff et al., 2014). These are G-protein-coupled receptors
(GPCRs) of the rhodopsin family (also known as family A
GPCRs). The NK2R (neuropeptide K receptor) is of historical
interest since it was the first neuropeptide receptor to be cloned
(Masu et al., 1987). Signaling through the NK receptors is
diverse and complex. For example, the ligand-activated NK1R
initiates G-protein mediated signaling that can lead to (1)
activation of phospholipase C (PLC), which results in formation
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FIGURE 3 | Scheme of human tachykinin precursors (Tac1, Tac3, and Tac4 and their splice variants). Boxes and lines show exons and introns, respectively. NPK
and NPg contain NKA sequences indicated by the red box at C-terminus, the N-termini of NPK and NPγare represented by pink boxes, and brown boxes represent
EKC or EKD that are not tachykinins. In addition, signal peptides are indicated by blue boxes. Bars indicate tachykinin or natalisin peptides that are part of multiple
exons: NKA, NPK, NPγ, EKA, EKB, EKC, EKD, respectively. The Tac4 peptides are designated endokinins A - D (EKA – EKD); hemokinin-1 (HK) represents the
C-terminal portion of EKA. The N-terminus of EKA is shown as pink boxes. Primary sequence data from Steinhoff et al. (2014).
of inositol trisphosphate (IP3) and diacylglycerol (DAG),
mobilization of intracellular stores of Ca2+, and activation
of PKC; (2) activation of adenylyl cyclase (AC), resulting in
formation of cAMP, and activation of PKA; or (3) activation
of phospholipase A2 and production of arachidonic acid
(Steinhoff et al., 2014).
In mammals, TKs play roles as neuromodulators/
cotransmitters in central brain circuits, as well as in pain,
stress, anxiety, depressive disorder, aggression, memory
formation, inflammation, cancer, immune function, gut function,
hematopoiesis, sensory processing, reproduction and cytokine
and hormone regulation [see (Otsuka and Yoshioka, 1993;Felipe
et al., 1998;Hökfelt et al., 2001;Holsboer, 2009;Onaga, 2014;
Steinhoff et al., 2014;Lénárd et al., 2018;Zieglgänsberger, 2019)].
Substance P was mapped to neurons in the rat nervous
system early on (Hökfelt et al., 1975, 1977;Ljungdahl et al., 1978).
Now, we know that the distribution of SP and other TKs,
as well as their receptors, is widespread and plastic. Receptor
expression is regulated by various transcription factors under
different physiological states. For instance, the receptors can be
upregulated during inflammation via the transcription factor
NF-κB (Onaga, 2014;Steinhoff et al., 2014). SP and NKA and
their receptors are not only widely distributed throughout the
central and peripheral nervous system, but also in many other
tissues including dermal tissue, gastrointestinal tract, as well as
the respiratory, urogenital and immune systems (Hökfelt et al.,
2001;Onaga, 2014;Steinhoff et al., 2014). Whereas SP and NKA
are expressed throughout the brain in mammals, NKB is found
mainly in the hypothalamus and spinal cord. Furthermore, SP
is present in brain circuits that are involved in the processing of
anxiety, such as the amygdala, septum, mid-brain, periaqueductal
gray, hippocampus, and hypothalamus (Holsboer, 2009).
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TABLE 1 | Human tachykinins.1
Tachykinin Gene2Receptor Amino acid sequence
Substance P Tac13NK1R RPKPQQFFGLMa
Neurokinin A Tac1 NK2R HKTDSFVGLMa
Neuropeptide K Tac1 NK2R DADSSIEKQVALLKALYGH
GQISHKRHKTDSFVGLMa
Neuropeptide γTac1 NK2R DAGHGQISHKR
HKTDSFVGLMa
Neurokinin B Tac3 NK3R DMHDFFVGLMa
Hemokinin-1 Tac44NK1R TGKASQFFGLMa
Endokinin-A Tac4 NK1R DGGEEQTLSTEAETWVIVALEEGAG
PSIQLQLQEVKTGKASQFFGLMa
Endokinin-B Tac4 NK1R DGGEEQTLSTEAETWEGAQ
LQLQEVKTGKASQFFGLMa
1Sequence and receptor data from Onaga (2014);Steinhoff et al. (2014). The
sequences of the Tac1 and Tac3 derived peptides are conserved in humans, mouse
and rat. 2These are also known as Ppt-a, Ppt-b and Ppt-c. 3Tac1 gene gives rise
to four splice forms: a, b, g, and d, see Figure 3.4Tac4 gene also gives rise to four
splice forms, a, b, g, and d (see Figure 3), and two additional peptides (Endokinin-C
and D) that are not TKs.
As another example, in zebrafish, Tac1 transcript has been
mapped to neurons in the olfactory bulb, telencephalon, preoptic
region, hypothalamus, mesencephalon, and rhombencephalon,
whereas Tac3a was observed in the preoptic region, habenula and
hypothalamus and Tac3b predominantly expressed in the dorsal
mesencephalon (Ogawa et al., 2012). Additional details of SP and
NKA distribution are beyond the scope of this review.
A few further examples of TK signaling are given here
that are of interest for the discussion of TK functions in
invertebrates in later sections. Certain taste cells express NK1R,
and SP appears to regulate responses not only to toxins, but
also to tastants: spicy foods stimulate SP release to enhance
umami taste reception (Onaga, 2014). In the dorsal horn of
the spinal cord, SP modulates nociceptive signals relayed to
the brain, but also in pain-processing areas of the brain cortex
(Felipe et al., 1998;Zieglgänsberger, 2019). NKB regulates
hormone (e.g., gonadotropin-releasing hormone, GnRH) release
in the hypothalamus (Steinhoff et al., 2014). NKRs are densely
distributed in the rat olfactory bulb and it was shown that SP acts
to depress neuronal activity in glomerular neurons, by triggering
release of GABA (Olpe et al., 1987), similar to TKs and GABA
in the antennal lobe of Drosophila (Ignell et al., 2009;Ko et al.,
2015). The intestine is supplied by processes from TK-expressing
neurons in dorsal root ganglia, or from local neurons (Hökfelt
et al., 2001). NKRs are widely expressed in the intestine (in
a cell-specific manner) by enteric neurons, intestinal muscle,
epithelium, vasculature as well as immune system. TK signaling
in the gut thus influences motility, electrolyte and fluid secretion,
as well as vascular and immune functions (Hökfelt et al., 2001).
Recently, all NKRs were also shown to be expressed in genital
organs and cells including the testis, sperm, ovary, granulosa cells,
cumulus cells, and the uterus, and shown to be involved in sperm
motility and reproduction (Pinto et al., 2010, 2015;García-Ortega
et al., 2014;Candenas et al., 2018;Blasco et al., 2019).
Substance P is also known to activate three Mas-related
GPCRs (Mrgprs), a promiscuous group of receptors underlying
itch: human MRGPRX2, mouse MrgprA1, and mouse MrgprB2
(Bader et al., 2014). It is clear that the Mrgpr group is entirely
separated from the TKR group (Bader et al., 2014). Interaction
of SP with the Mrgprs induces elevation of intercellular Ca2+
(Azimi et al., 2016). The EC50 value of SP for human MRGPRX2
is approximately 150 nM, while EC50 values of SP for mouse
MrgprA1 and MrgprB2 are about 5 µM and 50 µM, respectively
(Azimi et al., 2016). Interestingly, analyses using NK1R knockout
mice suggested that SP induces itch via Mrgprs rather than the
NK1R (Azimi et al., 2017). Mrgprs are specific to mammals,
suggesting that new SP-recognizing receptors arose during
mammalian evolution.
TKs and Receptors in Protochordates
and Non-mammalian Vertebrates
Genomes of non-mammalian vertebrates possess receptors that
are homologous to NK1R – NK3R (Biran et al., 2012;Satake
et al., 2013). Likewise, several genes encoding TK homologs are
present in non-mammalian vertebrate species. Tac1 and Tac3
have also been identified from zebrafish, and the Tac3 prototype
gene appears to have duplicated to give rise to Tac3a and Tac3b
(Biran et al., 2012) as shown in Figure 4. In addition, two Tac3
have also been characterized from an eel, Anguilla anguilla, that
is a basal vertebrate (Campo et al., 2018). Due to teleost-specific
whole genome duplication multiple Tac3 genes were generated
in teleost fish (Moriyama and Koshiba-Takeuchi, 2018). Tac3a
of zebrafish encodes not only an NKB (NKBa), but also an
NKF that is a piscine-specific TK (Biran et al., 2012). Tac3b of
zebrafish encodes both an NKB (NKBb) and an NKF, although
NKBb contains an FVGLLamide sequence at the C-terminus
that differs from TK consensus sequence FXGLMamide (Biran
et al., 2012). Gene duplication of zebrafish TK receptor genes
has also occurred, resulting in two NK1R genes (Tacr1a, Tacr1b)
and three NK3R genes (Tacr3a, Tacr3b, and Tacr3c) (Biran et al.,
2012). Both TACR3a and TACR3b are efficiently activated by
zebrafish NKBa and NKF, and their interaction induces both
elevation of intercellular Ca2+and production of cAMP (Biran
et al., 2012). EC50 values of NKBb for TACR3a and TACR3b are
50–100 fold higher than that of NKBa for TACR3a and TACR3b
(Biran et al., 2012). It is not clear whether homologs of HK and
EKs are present in non-mammalian vertebrates, although it was
proposed that Tac4 is present in fish, including zebrafish, Danio
rerio (Biran et al., 2012).
More than 20 TKs have been identified from skin secretion
of frogs including, Odorrana grahami,Rana chensinensis,
Theloderma kwangsiensis, Kassina senegalensis, and Physalaemus
fuscumaculatus (Supplementary Table S3). These skin TKs
possess the characteristic TK consensus sequence FXGLMamide
(Bertaccini et al., 1965;Anastasi et al., 1977;Li et al., 2006;
Wu et al., 2013;Zhang et al., 2013). The frog skin TKs are
likely to act as exogenous factors, for instance as antimicrobial
substances, rather than endogenous neuropeptides or hormones.
An endogenous tachykinin has also been isolated from the brain
of the frog, Rana ridibunda with a sequence homologous to
that of NKB (O’Harte et al., 1991). Moreover, Tac1 and Tac3
of the frog, Xenopus tropicalis, have been predicted (registered
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FIGURE 4 | Schemes of representative non-mammalian tachykinin precursors and arthropod natalisin (NTL) precursors. Boxes and lines show exons and introns,
respectively. Red boxes represent tachykinins, and yellow boxes indicate natalisins (signal peptides are indicated by blue boxes). Peptides with deviating sequences
are shown in different shades of gray. NKBb is not a tachykinin. DTK6 also differs from Drosophila TKs (has a FVAVRa C-terminus) and has not been confirmed by
mass spectrometry. Note that the spider mite TK1 precursor has both a TK and two NTLs; also note that the NTL sequences are only predictions (Veenstra et al.,
2012). The spider mite peptide X has the sequence ARPFAAMLamide distinct from both TKs and NTLs. Primary sequence data from Veenstra et al. (2012).
in NCBI databases). The X. tropicalis Tac1 encodes an SP-
like and an NKA-like peptide, while Tac3 gene encodes an
NKB-like and an NKF-like peptide. Interestingly, the sequence
of the T. kwangsiensis skin TK is identical to that of the
X. tropicalis SP-like peptide, except for two amino acid residues.
The sequence of the K. senegalensis skin TK is also similar to that
of SP (Supplementary Table S3). The skin TKs are amphibian-
specific, suggesting that TKs acquired new functions in the
amphibian lineage.
As shown in Figure 4 and Supplementary Table S1, two
TKs (CiTK-I, CiTK-II) were identified from the ascidian
(protochordate), Ciona intestinalis (Satake et al., 2004). Like
vertebrate TKs, CiTKs contain a C-terminal FXGLMamide
(Satake et al., 2004), suggesting that the FXGLMamide sequence
of TKs is highly conserved in Olfactores (vertebrates and
ascidians). Since the ascidians are among the basal chordates, the
CiTk gene is likely to correspond to a prototype of vertebrate
TK genes. This single CiTk gene in Ciona encodes CiTK-I
and CiTK-II (Satake et al., 2004;Figure 3B), suggesting that
gene duplications of a prototype TK gene have occurred in the
vertebrate lineage, resulting in Tac1, Tac3, Tac4, and amphibian
skin TK genes. Furthermore, CiTK-I and -II are located in the
same exon of the CiTk gene (Satake et al., 2004), indicating
that splice variants of the CiTk gene are absent (Figure 4).
Therefore, alternative splicing of the TK gene also emerged
during vertebrate evolution.
Homology search for mammalian NK1R - NK3R sequences
using a C. intestinalis database2, showed that only one
homologous receptor is present in the ascidian (Satake et al.,
2004). This receptor, CiTKR, can be activated by CiTKs
(Satake et al., 2004), indicating that it is an authentic TK
receptor. Phylogenetic analysis reveals that the CiTKR is sister
2http://ghost.zool.kyoto-u.ac.jp/SearchGenomekh.html
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FIGURE 5 | Structure of TK and natalisin (NTL) precursors from two
tardigrades (Hypsibius dujardini and Ramazottius varieornatus). Red boxes
represent tachykinins, and yellow boxes indicate natalisins (signal peptides are
indicated by blue boxes). These precursors each contain one TK and one
predicted NTL. Note that the NTL sequences are predictions and have not
been confirmed by mass spectrometry. Compiled from sequence data in
Koziol (2018).
to the vertebrate TK receptor clade, which comprises NK1R -
NK3R (Figure 7). These results suggest that NK1R – NK3R
arose via duplication and diversification in the vertebrate
lineage (Figure 7).
TKs and Their Receptors in Insects and
Other Protostome Invertebrates
Tachykinins have been identified in a wide range of
invertebrates, including annelids, mollusks, arthropods,
tardigrades, echinoderms and tunicates, and tentatively in
nematodes (see Supplementary Table S1). Several of these
were isolated biochemically, others cloned, but most were
identified by bioinformatics and subsequently confirmed by mass
spectrometry. However, many TKs listed in the Supplementary
Table S1 have only been predicted from sequences identified
from genomes and transcriptomes, based on similarity searches
and await confirmation by mass spectrometry. There are some
groups of invertebrates where TKs have not been identified or
where sequences are only remotely similar to TKs. For instance
in flatworms (Platyhelminthes) and cubomedusae (Cnidaria)
no TKs have yet been discovered (McVeigh et al., 2009;Nielsen
et al., 2019), and in sea anemones (Cnidaria) and nematodes (e. g.
C. elegans) the “TK sequences” are not clearly TK-related (Ohno
et al., 2017;Palamiuc et al., 2017;Hayakawa et al., 2019), see
Supplementary Table S1. In fact, the proposed C. elegans TK-like
receptor (NPR-22) is more closely related to RYamide/Luqin
receptors than to TK-like receptors, and luqin-like peptides
(from the LURY-1 precursor) are found in the worm and were
shown to activate the receptor (Ohno et al., 2017;Yañez-Guerra
et al., 2018). The previously proposed ligand (FMRFamide-
like peptide 7, FLP-7) activates NPR-22 only at micromolar
concentrations in a heterologous assay (Mertens et al., 2006;
Palamiuc et al., 2017), suggesting that it is not a ligand [see
(Ohno et al., 2017)]. However, it remains to be tested whether
FLP-7 peptide is an NPR-22 ligand in vivo. Also, the C. elegans
TK-like peptide derived from NPL-8 (SFDRMGGTEFGLM),
does not activate the NPR-22 receptor (Mertens et al., 2006).
Thus, the presence of a TK signaling system in C. elegans is still
unresolved. However, TK-like receptors are found in Cnidaria
(Anctil, 2009;Krishnan and Schiöth, 2015) (bioinformatics
only), so the origin of TK signaling could possibly be traced to
the common ancestor of Bilateria and Cnidaria. The presence of
TK receptors has been demonstrated in the two major clades of
Bilateria, the Nephrozoa (protostomes and deuterostomes) and
its sister group the Xenacoelomorpha, that include Xenoturbella,
Nemertodermatida, and Acoela (Thiel et al., 2018). In the
Xenacoelomorpha, the presence is based on bioinformatics only.
With a few exceptions, each species has one gene encoding a
TK precursor with multiple copies of TK peptides. As exceptions,
two precursor genes were found in e.g., the limpet Lottia gigantea
(Veenstra, 2010), the polychaete worm Platynereis dumerilii
(Conzelmann et al., 2013), the crab Carcinus maenas (Christie,
2016), the tardigrade Hypsibius dujardini (Koziol, 2018) and
the spider mite Tetranychus urticae (Veenstra et al., 2012;
Supplementary Table S1). The organization of Drosophila and
spider mite TK precursors is shown in Figure 4 and that of the
mosquito Aedes aegypti in Figure 2B. The number of peptides
that can be cleaved from invertebrate TK precursors range from
1 in tardigrades (Koziol, 2018;Figure 5) to 15 in the cockroaches
Leucophaea maderae and Periplaneta americana (Predel et al.,
2005). Commonly, these peptides all have different, but related
sequences (designated paracopies). In a few cases, the precursor
only has several identical TKs, like in the crayfish Procambarus
clarkii, which has seven CabTRP1 (Yasuda-Kamatani and Yasuda,
2004). The TKs are generally between 9 and 11 amino acids long,
but a few have only 6, and others up to 18 as in cockroaches
(Muren and Nässel, 1996;Predel et al., 2005), or even 37 residues
as predicted in some scorpions and spiders (Veenstra, 2016).
Interestingly, the N-terminally extended TKs of cockroaches have
internal dibasic cleavage sites and it appears as if in the brain
these are more likely to be processed and, thus, generate the
shortened TKs, whereas the extended TKs are normally found in
the midgut (Muren and Nässel, 1996, 1997;Winther et al., 1999;
Predel et al., 2005).
All TKs are amidated, but only very few have been detected
that may be N-terminally blocked by pyroglutamate (pQ), for
instance in hemipteran bugs and the bivalve mollusk Anodonta
cygnea (Supplementary Table S1). In insects and many other
arthropods, it is common to find TKs with an N-terminal
proline (P) in the second position (e.g., Drosophila DTK-2,
APLAFVGLRa). This is likely to render the peptides sensitive
to proline-specific dipeptidyl peptidase (DPP-IV) cleavage and
inactivation (Nässel et al., 2000;Isaac et al., 2009). Thus, TKs
can be specifically inactivated by DPP-IV selectively located in
regions of the CNS or in the periphery (Nässel et al., 2000).
Other peptidases that have been shown to inactivate TKs are
nephrilysins, angiotensin converting enzymes and deaminases
[see (Isaac et al., 2002, 2009)].
Two putative TK receptors were cloned from Drosophila
before the endogenous ligands were known (Li et al., 1991;
Monnier et al., 1992). Both receptors displayed significant
similarities to mammalian TK receptors. One of these, designated
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FIGURE 6 | A cladogram showing the occurrence of tachykinin and natalisin signaling systems in Bilateria and Cnidaria. Sequence logos of the peptides have also
been provided. These were constructed using the final 10 amino acids at the C-terminus. Note that C-terminal amidation is not shown; it is represented by the
amidation signal G. Species in which the receptors have been functionally characterized are indicated by asterisk. Note that the natalisin signaling system appears to
have arisen in the lineage leading up to tardigrades and arthropods. The tachykinin-like peptide sequences in Asterias rubens, Caenorhabditis elegans, and
Nematostella vectensis diverge from the canonical TK sequences in other phyla and should probably not be classified as TKs (see text). In C. elegans a TK receptor
has not been functionally characterized, although an FLP-7/NPR-22 signaling system has been proposed (Palamiuc et al., 2017), but shown to represent a
luqin/RYamide signaling system (Ohno et al., 2017). The peptide encoded by the TK2 precursor in Hypsibius dujardini looks more similar to arthropod natalisins.
Precursors encoding TK-like peptides have not yet been identified in Branchiostoma floridae and Saccoglossus kowalevskii. However, TK-like receptors are present
in all the animals presented here.
DTKR (CG7887) was confirmed as a receptor for endogenous
Drosophila TKs (DTK-1-5) (Birse et al., 2006), the other
NKD (CG6515) was first shown to respond to DTK-6, but
not the other Drosophila TKs (Poels et al., 2009). DTK-
6 has an FVAVRamide C-terminus instead of the common
FX1GX2Ramide. Surprisingly, it turned out several years later
that NKD is a receptor for a novel family of neuropeptides
called natalisins (NTL) that in Drosophila have a consensus
sequence of FX1X2X3Ramide (Jiang et al., 2013). One of these
peptides, NTL4, has an FFATRamide, remotely similar to DTK-
6, and indeed at high concentrations NTL4 activated the TK
receptor DTKR (Jiang et al., 2013). The same authors also
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FIGURE 7 | Phylogeny of tachykinin and natalisin receptors. RYamide and luqin receptors were used as outgroup to root the tree. Amino acid sequences of
full-length receptors were used for the analysis. Sequences were aligned using the MAFFT (E-INS-i algorithm and BLOSUM30 scoring matrix) and the phylogenetic
tree constructed using the FastTree plugin in Geneious Prime (2019). Receptors that have been functionally characterized are indicated by a symbol before the
species name. Note that in another annelid, Urechis unicinctus (among Lophotrochozoans), the TK receptor has been functionally characterized (not shown here).
The figure was constructed in MEGAX. Sequences used to generate the phylogeny are provided in Supplementary Material Text File S1.
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FIGURE 8 | TK in the Drosophila brain. (A) Schematic of neuronal TK distribution in the adult Drosophila brain (frontal view). Neuronal cell bodies are shown in
different colors (see legend in figure) to indicate those that have been studied functionally in some detail (blue and red shades), versus those that remain unexplored
(black). The light red neurons (SMP, MPP, LPP1a) innervate different layers of the fan-shaped body of the central complex (Kahsai and Winther, 2011) and modulate
explorative walking (Kahsai et al., 2010b). The dark blue ones (DC1, DC2) are local neurons of the antennal lobe, some of which coexpress GABA, and are part of
circuitry that regulates odor sensitivity in olfactory sensory neurons (OSNs) (Ignell et al., 2009). In male flies the light blue neurons (LPP1b) express FruMand probably
acetylcholine (Ach) and regulate levels of aggression (Asahina et al., 2014). The dark red ones (ITPn) are lateral neurosecretory cells (LNCs) with axon terminations in
the corpora cardiaca-corpora allata, anterior aorta and intestine (Kahsai et al., 2010a). These cells (ITPn) co-express TK, ion transport peptide (ITP) and short
neuropeptide F (sNPF) and regulate aspects of metabolic and water homeostasis (Kahsai et al., 2010a;Galikova et al., 2018). Arrow indicates axon destined for
retrocerebral complex of the black neurons LPP2 and TC1 neurons send axons to the pars intercerebralis (PI) and dorsal protocerebrum (Lundquist et al., 1994;
Winther et al., 2003), the DNs were assumed to be descending neurons (Winther et al., 2003), and resemble natalisin-producing ICLI neurons shown in
Supplementary Figure S5 (Jiang et al., 2013). The branching of the neurons associated with the optic lobes (OL) and subesophageal zone (SEZ) has not been
unraveled. The terminology (except ITPn) is from Winther et al. (2003) and specification of neurons compiled from papers cited above. (B) Schematic of TK
distribution in some neuropil regions of the Drosophila brain. FB, fan-shaped body, other acronyms as in (A). Modified from Nässel (2002).(C) TK immunoreactive
neurons in brain and ventral nerve cord of third instar larva of Drosophila, slightly edited from Winther et al. (2003). Blue arrows indicate a descending neuron. T3,
third thoracic neuromere; A1-A8 abdominal neuromeres.
showed that DTK-6 at high concentrations activates the NTL
receptor NTLR. In many insects, receptors of both DTKR-
and NTLR-type have been identified (Jiang et al., 2013). In
other invertebrates, such as for instance annelids (Urechis) and
mollusks (Octopus) only receptors of DTKR type are known
(Kawada et al., 2002;Kanda et al., 2007), suggesting that the
NTL signaling system arose in the arthropod lineage (Jiang et al.,
2013). However, TK-like precursors with NTL-like peptides are
found in the spider mite (chelicerate) as well as tardigrades; the
latter suggesting that the NTL signaling might also be present
outside arthropods. Natalisin signaling will be discussed in a
separate section.
Some invertebrate TKs act on exogenous TK receptors in
prey animals. TKs with FQGMRa C-termini (Figure 2 and
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FIGURE 9 | Role of TK signaling in food odor sensing in the antennal lobe of Drosophila.(A) TK peptides are expressed in local neurons (LN) of the antennal lobe
and innervate most glomeruli. Two glomeruli are shown here (DM1 and DM5). Of these DM1 is mediating food odor attraction (Or42b) and DM5 food odor aversion
(Or85b). (B) Image of TK immunoreactive LNs (green) in the clusters DC1 and DC2 innervation antennal lobe (AL). (C) Role of TK signaling in the DM5 glomerulus,
which relays aversive odor signals from olfactory sensory neurons (OSN) that express odorant receptors Or85b to DM5 projection neurons (PN) which in turn signal
to higher order neurons that control food search. In the fed fly the circulating level of insulin-like peptide (DILP) is high, which suppresses expression (transcription) of
the TK receptor DTKR. When DTKR signaling is low there is no suppression of Ca2+channel activity and therefore release of acetylcholine (ACh) is strong when the
OSN is activated and as a consequence the DM5 PN relays strong aversive signals and food search is reduced. (D) In the hungry fly the DILP level is low, DTKR
expression is high and therefore TK signaling activates DTKR and the OSN releases less ACh resulting in suppressed activation of the aversive DM5 PN and
therefore increase food search. (E) A scheme showing the combined signaling from the DM1 and DM2 signaling pathways that increase food search in hungry flies
with low circulating insulin. In hungry flies the aversive DM5 odor pathway is inactivated resulting in increased food search (as detailed in Figure 7C). In the DM1
pathway (food odor attraction) signaling with short neuropeptide F (sNPF) and its receptor sNPFR is increased in hungry flies due to low insulin and increased
expression of the sNPFR. This leads to presynaptic potentiation of the ACh signaling and increased activation of DM1 PNs, resulting in increased food search. The
panels (A,C–E) were redrawn from figures in Ko et al. (2015) and Jékely et al. (2018).
Supplementary Table S2) are produced by venom glands of the
Jewel wasp Ampulex compressa and injected into the cockroach
brain where action on the TK receptors leads to paralysis
(Arvidson et al., 2019). Interestingly, these wasp venom TKs
are injected as a precursor protein in the low pH venom,
and not as cleaved peptides; only in the cockroach brain
with neutral pH they will be slowly liberated to act on TK
receptors (Arvidson et al., 2019). Other TKs with C-terminal
FXGLMamide are produced in salivary glands of the mosquito
Aedes aegypti (sialokinins I and II), and the cephalopods Eledone
moschata (eledoisin) and Octopus vulgaris (OctTK-I and II)
(Erspamer and Anastasi, 1962;Champagne and Ribeiro, 1994;
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Kanda et al., 2003). Presumably these TKs cause vasodilation
in vertebrate prey animals [see (Erspamer and Erspamer, 1962;
Beerntsen et al., 1999)]. The sequences of gland TKs are shown
in Figure 2 and Supplementary Table S2.
A Case of Novel Ligands for an Insect TK
Receptor
Although most peptides and their cognate receptors co-evolve,
there are a few interesting cases where receptors have adopted
novel structurally unrelated ligands in addition to their original
ligands. A well-known example is the Drosophila sex peptide,
produced in male accessory glands and transferred to the female
during copulation (Wolfner, 2002;Kubli, 2003). Sex peptide
was adopted as an additional ligand for the myoinhibitory
peptide (MIP) receptor (Kim et al., 2010). The Drosophila MIP
receptor is the only known receptor for sex peptide. Another
example, again in Drosophila, is the pigment-dispersing factor
(PDF) receptor that has adopted DH31 as an additional ligand
(Shafer et al., 2008;Goda et al., 2016). However, unlike sex
peptide, DH31 also exerts its effects by binding to its own
specific DH31 receptor (Johnson et al., 2005), suggesting that
the PDF receptor is promiscuous. A similar phenomenon has
been discovered for the silkmoth Bombyx mori TK receptor
(BNGR-A24), which seems to have adopted ion-transport peptide
(extended ITPL isoform in particular) as a novel additional ligand
(Nagai-Okatani et al., 2016). Bombyx ITPL is a large protein
(79 amino acids), comprising 6 cysteine residues, which form
three disulfide bridges, and is thus structurally very dissimilar
to tachykinins (Roller et al., 2008;Nagai-Okatani et al., 2016).
Nonetheless, Bombyx ITPL and TKs appear to be orthosteric
ligands of the Bombyx TK receptor (BNGR-A24) based on
heterologous and homologous cell culture experiments (He et al.,
2014;Nagai-Okatani et al., 2016). Moreover, activation of BNGR-
A24 by ITPL is coupled to the cGMP pathway, whereas BNGR-
A24 activation by TKs can activate different second messenger
pathways in a cell-type specific manner. More specifically, TK-
mediated activation of BNGR-A24 in BmN cells has no effect
on cAMP and cGMP levels, but if the receptor is expressed in
HEK293 and Sf21 cells causes an increase in cAMP and Ca2+
levels (He et al., 2014;Nagai-Okatani et al., 2016). Thus, the two
ligands of the Bombyx TK receptor may activate distinct second
messenger pathways, at least in vitro. Since ITP or ITPL receptors
have not been identified in any other species besides Bombyx,
it remains to be determined if this phenomenon is widespread
amongst insects, or whether it is just restricted to Bombyx.
TKs and Their Receptors in
Deuterostome Invertebrates
TK-like receptors have also been mined from the genomes
and transcriptomes of invertebrate deuterostome phyla such as
Cephalochordata (e.g., Branchiostoma floridae), Hemichordata
(e.g., Saccoglossus kowalevskii) and Echinodermata (e.g., Asterias
rubens) (Jekely, 2013;Mirabeau and Joly, 2013;Yañez-Guerra
et al., 2018). Phylogenetic analysis suggests that TK-like receptors
and luqin/RYamide-type receptors arose by gene duplication
in a common ancestor of the Bilateria (Yañez-Guerra et al.,
2018). Precursors encoding TK-like peptides have also been
predicted in the starfish, Asterias rubens, and brittle stars
(Figure 1 and Supplementary Table S1) (Semmens et al., 2016;
Zandawala et al., 2017). However, the predicted TK-like peptides
from A. rubens with an XXGL/IFamide C-terminus diverge
substantially from FXGXRamide peptides of invertebrates, as
well as from TKs of the protochordate Ciona intestinalis and
vertebrates (FXGLMamide) (Semmens et al., 2016). Interestingly,
the C-terminus of A. rubens (XXGL/IFamide) is somewhat
similar to the proposed C. elegans tachykinin-like peptides
(XMVRFamide) (Palamiuc et al., 2017), with peptides of both
species having an Famide C-terminus and lacking the conserved
phenylalanine residue in 5th position from the C-terminus.
However, as mentioned above, the C. elegans TK-like receptor
is more similar to RYamide/Luqin-like receptors, so it remains
to be determined whether the predicted TK-like peptides
in echinoderms are bona fide endogenous ligands for the
echinoderm TK-like receptors. Moreover, sequences encoding
TK-like receptors have been identified in the genomes and/or
transcriptomes of hemichordates and cephalochordates (Jekely,
2013;Mirabeau and Joly, 2013;Figure 6). However, TK-like
peptides have not yet been identified in these taxa. Perhaps
the difficulty in discovering these peptides can be attributed
to substantial diversification in the canonical sequence, which
would render the homology-based search protocols ineffective.
EVOLUTION OF TACHYKININ
SIGNALING COMPONENTS
We show a cladogram of TKs (Figure 6) and phylogenetic
analysis their receptors (Figure 7) in the animal kingdom and the
occurrence of natalisin signaling in some groups. TK signaling
is evolutionary ancient (Figure 6) and is one of several peptide
families that emerged before the split of deuterostomes and
protostomes (Jekely, 2013;Mirabeau and Joly, 2013). A few recent
studies suggest that it might be more ancient than previously
thought. TK-like receptors were recently found in genomes
of Xenacoelomorpha, which is a sister group of Nephrozoa
(comprising deuterostomes and protostomes) (Thiel et al., 2018).
However, no TK-like ligands were identified in these genomes.
A TK-like GPCR has also been predicted in the genome of
the sea anemone Nematostella vectensis, but this receptor is
more closely related to other Nematostella neuropeptide GPCRs
than it is to bilaterian TK receptors (Krishnan and Schiöth,
2015;Thiel et al., 2018). Most protostomes have a single TK
receptor but protostomian TK precursors encode multiple TK
peptides (Figure 7). Thus, it appears that protostomian TKRs
can all be activated by the different TKs, as shown already in
Drosophila and Bombyx (Birse et al., 2006;Jiang et al., 2013;
Nagai-Okatani et al., 2016). Our phylogenetic analysis shows
that a single TK-like receptor is also found in tardigrades
(Figure 7;Koziol, 2018). Interestingly, tardigrades have 2 TK-
like precursors, one of which encodes a peptide with sequence
similarity to TKs and another one, which encodes a NTL-
like peptide (Figure 5;Koziol, 2018). This suggests that NTL
signaling may have arisen by the duplication of TK gene first
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and a subsequent duplication and diversification of its receptor.
Interestingly, the spider mite genome encodes multiple NTL-like
receptors and a single TK receptor. In addition, it possesses two
TK-like precursors, one of which contains TK-like and NTL-
like peptides and another precursor with only TK-like peptides
(Figure 5). This perhaps indicates a more advanced point in
the diversification of the NTL-signaling, as the receptors now
seem to have duplicated. Additional genomes of basal arthropods,
onychophores and tardigrades need to be examined to determine
the nature of TK-like and NTL-like signaling present in these
animals before we can establish the precise lineage in which the
NTL-signaling arose.
In deuterostomes, at least ancient Olfactores (vertebrates
and ascidians) acquired a TK receptor that recognized a TK
harboring the C-terminal FXGLMamide motif. The three
subtypes of TK receptors, namely NK1R, NK2R, and NK3R,
appear to have arisen following the whole genome duplications
in the vertebrate lineage. Furthermore, these subfamilies might
have acquired ligand selectivity during their diversification along
with the generation of TK subtypes. The current missing pieces
are echinoderm, acorn worm, and amphioxus counterparts,
because canonical TKs have not yet been identified in genomes
and/or transcriptomes of these deuterostome invertebrates.
However, multiple TKRs are present in echinoderms and
hemichordates suggesting additional independent gene
duplication events within these lineages. In Supplementary
Figure S1 we show multiple sequence alignments of select TK
and natalisin receptors.
TACHYKININS IN INVERTEBRATES,
DISTRIBUTION AND FUNCTIONS
Overview of Functional Diversity From
Early Studies
The first TKs isolated from insects were purified with the aid
of a hindgut contraction assay that had also been utilized for
first discovery of numerous other insect neuropeptides (Holman
et al., 1990, 1991;Schoofs et al., 1990b). TKs from the annelid
worm Urechis unicinctus were also purified with the aid of
a muscle contraction assay (Ikeda et al., 1993). Thus, it was
shown early that TKs are myostimulatory on a variety of
muscles in the body wall, oviduct, foregut, hindgut, as well
as heart [see (Ikeda et al., 1993;Schoofs et al., 1993;Nässel,
1999;Sliwowska et al., 2001)]. Examples of other functions
established before employment of genetic tools are modulation
of network activity in the stomatogastric ganglion of crustaceans
[(Blitz et al., 1995), reviewed in Nusbaum and Blitz (2012),
Nusbaum et al. (2017)], activation of dorsal unpaired median
neurons in locust (Lundquist and Nässel, 1997), stimulation of
release of adipokinetic hormone from locust corpora cardiaca
(Nässel et al., 1995b), diuretic action on Malpighian tubules
of locust L. migratoria and moth Manduca sexta (Skaer et al.,
2002;Johard et al., 2003) and presynaptic inhibition of crayfish
photoreceptors, likely as a co-transmitter of GABA (Glantz et al.,
2000). From numerous in vitro studies, there is no evidence
that the different paracopies of TKs in a species have any major
differential activities or functions, except possibly DTK-6 in
Drosophila, but it should be noted that the presence of this
mature peptide has not been verified by mass spectrometry.
Additional functions of TKs discovered using various approaches
are discussed separately in the context of different species in
sections “Distribution and Function of TKs in Invertebrates” and
“Functional Roles of TKs in Drosophila, Genetic Advances”.
Distribution and Function of TKs in
Invertebrates
Early work used antisera to substance P and other vertebrate
tachykinins to localize presumptive TK neurons in the CNS of
several invertebrates summarized in Nässel (1999). It should
be noted that the earliest of these studies were performed
before neuronal/intestinal TKs had been isolated and sequenced
in invertebrates. In retrospect, it appears that of the TK
antibodies used during this era, one monoclonal antibody (Cuello
et al., 1979) actually recognizes the invertebrate TKs [see (Blitz
et al., 1995;Johansson et al., 1999;Nässel, 1999)], whereas
the polyclonal ones, except anti-Kassinin (Lundquist et al.,
1994), seem to label other epitopes, at least in insects. Thus,
TK distribution in several crustaceans (Sandeman et al., 1990;
Schmidt and Ache, 1994;Blitz et al., 1995;Johansson et al.,
1999), and the horse shoe crab Limulus polyphemus (Chamberlain
and Engbretson, 1982;Mancillas and Selverston, 1985) is likely
to be correctly described in these earlier studies. The first
antisera to invertebrate TKs were raised against locust LomTK-I
(Nässel, 1993) and LomTK-II (Vitzthum and Homberg, 1998),
blowfly CavTKII (Nässel et al., 1995a) and cockroach LemTRP1
(Winther and Nässel, 2001) and these were subsequently used
in a large number of invertebrate species, some of which
are outlined below.
Insects
The neuronal distribution of TK immunoreactivity in the CNS
is in general fairly well conserved between insects studied,
whereas in other arthropods only some features seem to be
shared with insects. Characteristic of TK distribution in insects
is presence in neuronal processes in antennal lobes, central
complex, pars intercerebralis, dorsolateral protocerebrum, optic
lobes and subesophageal zone. First, we will outline the neuronal
localization of TK in Drosophila and a few other insects,
then move on to crustaceans, and snails. For these organisms,
except Drosophila, we also briefly describe TK functions.
Functional roles of TK signaling in Drosophila are described in
a separate section.
In the adult Drosophila brain, in situ hybridization and
immunolabeling revealed that there are more than 160 TK-
expressing neurons that can be divided up into 11 bilateral
groups and one unique pair (Figure 8A;Winther et al., 2003).
Ten large lateral neurosecretory cells (ITPn) express TK, as well
as two other peptides (short neuropeptide F, sNPF, and ion
transport peptide, ITP) (Kahsai et al., 2010a). The other TK
neurons are interneurons of different kinds innervating the fan-
shaped body of the central complex, the antennal lobes, the optic
lobes, pars intercerebralis, dorsal lateral protocerebrum and the
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subesophageal zone (Winther et al., 2003). Some of these TK
neuron clusters have been functionally investigated by genetic
manipulations (colored cells in Figure 8A), whereas the functions
of other clusters (black cells in Figure 8A) remain obscure.
Functional aspects will be discussed later in a separate section.
Details of some of the TK neurons are shown in Figure 8B. In the
third instar larva there are only about 44 neurons in the entire
CNS that are consistently labeled by TK antisera; 32 of these are
in the brain and SEZ (Figure 8C) (Siviter et al., 2000;Winther
et al., 2003). In both larvae and adults, enteroendocrine cells of
the midgut and anterior hindgut express TK (Siviter et al., 2000;
Veenstra et al., 2008;Veenstra, 2009).
In some cells in Drosophila, TK is colocalized with
other neuropeptides or GABA (Supplementary Table S4): in
neurosecretory cells (ITPn) with sNPF and ITP, in local neurons
of the antennal lobe with either GABA, allatostatin-A or
myoinhibitory peptide (MIP; also known as allatostatin-B) and
in midgut enteroendocrine cells with either neuropeptide F or
diuretic hormone 31 (Veenstra et al., 2008;Ignell et al., 2009;
Carlsson et al., 2010;Kahsai et al., 2010a). In addition, single
cell transcriptome sequencing of brain neurons shows that TK
is coexpressed with glycoprotein hormone beta 5 (GPB5) (Davie
et al., 2018). A more systematic screen of colocalized substances
in the insect CNS would probably make this list longer.
The blowfly Calliphora vomitoria displays a neuronal
distribution of TK very similar to that in Drosophila (Lundquist
et al., 1994). Studies of TK distribution in other insects reveal
many similarities, except that the numbers of neurons in the
different clusters vary between species, as shown next.
In the brain of the honeybee Apis mellifera TK distribution
was mapped by in situ hybridization (Takeuchi et al., 2004).
Neuronal cell bodies were revealed in association with the
central complex, antennal lobes and optic lobes, as in other
insects, but also associated with the mushroom body calyces.
The intrinsic mushroom body neurons were identified as the
small-type Kenyon cells (class I and II) (Takeuchi et al., 2004).
Later, immunolabeling also confirmed presence of TK in Kenyon
cells including their axons in the lobes (Heuer et al., 2012). The
distribution of TK transcript is spatially similar irrespectively of
sex, cast, or division of labor of workers: however, quantitatively
transcript levels are higher in queens and foragers than in nurse
and drone bees (Takeuchi et al., 2004). In bees, the TK in
mushroom bodies may be involved in regulation of foraging and
social behaviors (Takeuchi et al., 2004;Brockmann et al., 2009;
Boerjan et al., 2010). Also in other hymenopterans (Oya et al.,
2017) and in the beetle Tribolium castaneum (Binzer et al., 2014),
TK was identified in major subpopulations of Kenyon cells, but in
other studied insects there are so far no reports of such neurons
producing TKs. In the honeybee, quantification of neuropeptides
by mass spectrometry was performed after foraging nectar or
pollen (Brockmann et al., 2009). TK was among the three peptides
whose levels were most affected in association with foraging for
nectar or pollen.
In the moth Spodoptera litura, at least 80 TK neurons were
detected in the adult brain, and the innervation of the central
complex, the antennal lobes, pars intercerebralis, dorsal lateral
protocerebrum and the subesophageal zone is similar to that
in Drosophila (Kim et al., 1998; see Supplementary Figure S2).
Also a pair of large descending neurons was identified. A special
feature of the moth is the presence of TK expression in 8 median
neurosecretory cells with axon terminations in the retrocerebral
complex and anterior aorta (Kim et al., 1998). Similar median
neurosecretory cells (MNCs) were also seen in the moth Heliothis
virescens (Zhao et al., 2017), and the beetles Tenebrio molitor
and Zophobas atratus (Sliwowska et al., 2001). In another moth
Manduca sexta, the TK distribution in the brain (except the
MNCs) and intestine was found similar to S. litura and it was
shown that TK stimulates secretion in the Malpighian tubules
in vitro (Skaer et al., 2002).
The brains of the cockroach Leucophaea maderae and the
locust Locusta migratoria contain far larger numbers of TK
neurons, but the innervation pattern of brain regions is similar to
Drosophila and moth (Nässel, 1993;Muren et al., 1995;Vitzthum
and Homberg, 1998). In the L. maderae brain (without optic
lobes), about 360 TK neurons were found (Muren et al., 1995;
Supplementary Figure S3), and about 800 in the entire brain
of L. migratoria (Nässel, 1993). In contrast to Drosophila, there
are efferent TK neurons in the cockroach abdominal ganglia that
innervate the hindgut and TK neurons in the stomatogastric
ganglia that supply extensive axon terminations over the foregut
and midgut (Muren et al., 1995;Nässel et al., 1998). In locusts, TK
neurons in the lateral neurosecretory cell group send axons to the
corpora cardiaca where they contact cells producing adipokinetic
hormone (AKH) and it was shown that TKs induce AKH release
in vitro (Nässel et al., 1995b). These neurosecretory cells may
be analogous to the ITPn neurons in Drosophila (Kahsai et al.,
2010a), although a role in hormone release was not yet analyzed
in the fly. In both locust and cockroach midgut, endocrine cells
express TK, and in the locust there are also TK producing
endocrine cells in the six midgut ampullae at the base of the
Malpighian tubules (Muren et al., 1995;Winther and Nässel,
2001). TKs stimulate secretion in locust Malpighian tubules
(Johard et al., 2003). Calcium-dependent release of TK from the
cockroach and locust intestine could be induced by potassium
application, and TK was demonstrated in hemolymph, suggesting
that hormonal release of intestinal TK regulates tubules secretion
(Winther and Nässel, 2001). In locusts, several cases of
colocalization of TK and other peptides have been demonstrated.
The endocrines of the ampullae (but not in the rest of the midgut)
coexpress TK, diuretic hormone 44 (DH44) and FMRFamide-
like peptide, and TK was shown to stimulate secretion in locust
Malpighian tubules together with DH44 (Johard et al., 2003).
In certain central complex neurons there is co-expression of
TK and leucokinin and in others TK and octopamine or GABA
(Vitzthum and Homberg, 1998). Finally, sensory neurons of the
metathoracic legs co-express TK, allatotropin, FMRFamide-like
peptide and probably acetylcholine (Persson and Nässel, 1999;
Supplementary Table S4).
Another insect studied in some detail is the hemipteran blood-
sucking bug Rhodnius prolixus where a total of about 250 TK
immunoreactive neurons were found in the brain (Kwok et al.,
2005). These are distributed in the optic lobes and in several
other clusters in the midbrain. Interestingly, no TK containing
enteroendocrine cells were detected in this species, in contrast
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to many other studied insects, but the hindgut is innervated
by TK axons (Kwok et al., 2005). These TK axons also express
leucokinin, another myostimulatory peptide (Haddad et al.,
2018). Rhodnius TKs were shown to increase the basal tonus of
the hindgut, but also to increase the frequency and amplitude
of peristaltic contractions of the salivary gland, a tissue that
displays high levels of TK transcript, but no immunoreactive TK
(Haddad et al., 2018).
Some further functions of TKs in insects other than Drosophila
have been explored that might shed light on TK signaling
in general. In female burying beetles, Nicrophorus vespilloides,
neuropeptides were quantified in solitary virgins, individuals
actively parenting or post-parenting solitary adults to identify
neuropeptides associated with parenting (Cunningham et al.,
2017). TK was found as one of the few peptides associated with
active parenting. In several insects, including Drosophila, oriental
fruitfly, cockroaches and moths, TK seems to play a role in
modulation of olfactory sensory processing (Ignell et al., 2009;
Jung et al., 2013;Fusca et al., 2015;Ko et al., 2015;Gui et al.,
2017b;Lizbinski and Dacks, 2017). Other functions have not been
investigated in multiple species; however, immunocytochemistry
suggests some conservation of the distribution of TK in neurons
of specific brain centers, and intestine in insects and crustaceans
that might also reflect functional conservation.
Crustaceans
The TK distribution in the brain of a few crayfish, lobster and crab
species has been studied, mostly with a monoclonal antibody to
substance P (Goldberg et al., 1988;Sandeman et al., 1990;Schmidt
and Ache, 1994;Schmidt, 1997a,b), but one study also employed
antiserum to a cockroach TK that is nearly identical to crab TK
(Johansson et al., 1999). These studies have mostly focused on
TK neurons in the olfactory centers of the brain, but also the
stomatogastric nervous system.
As seen in Supplementary Figure S4, brain of crayfishes
possesses a pair of TK interneurons with large cell bodies
and extensive processes in the anterior deutocerebrum and
varicose branches among the cell bodies of a group of olfactory
interneurons in the lateral deutocerebrum (Sandeman et al., 1990;
Johansson et al., 1999). There is another pair of TK neurons
with deutocerebral cell bodies and processes in the neuropil
of the olfactory lobe, as well as larger numbers of small TK
neurons with processes in the olfactory and accessory lobes
(Sandeman et al., 1990;Johansson et al., 1999). TK neurons
were shown in all the neuropils of the optic lobes of the
crayfish and specifically a set of TK and GABA expressing
amacrine cells were identified in the lamina ganglionaris (Glantz
et al., 2000). This study shows that application of GABA
and TK to photoreceptor terminals in the lamina induces a
short-latency, dose-dependent hyperpolarization with a decay
time of a few seconds. TK also acts over several minutes to
reduce the photoreceptor potential to potentiate the action
of GABA (Glantz et al., 2000). In the American lobster, the
distribution of TK processes is in general similar to that
seen in insects with TK immunolabeling in the protocerebral
bridge, central body, olfactory (antennal) lobes, and anterior
median protocerebral neuropil (Langworthy et al., 1997). Like
in insects, midgut enteroendocrine cells in crabs also express TK
(Christie et al., 2007).
In decapod crustaceans the stomatogastric nervous system
(STN) consists of 25–30 neurons (depending on species) and
controls handling of ingested food. Most of these neurons
contribute to the activity in one or both of the neural networks in
the STN, which regulate (1) gastric mill (chewing) or (2) pyloric
circuit (pumping and filtering of food that has been chewed)
[see (Nusbaum et al., 2017)]. A pair of neurons (MCN1) that
innervate the stomatogastric ganglion produces the TK CabTRP-
Ia (Blitz et al., 1995;Christie et al., 1997). The MCN1s also
produce GABA and the peptide proctolin (Nusbaum et al., 2017).
It was shown that CabTRP-Ia and GABA released from MCN1
are critical for activation of the gastric mill rhythm, whereas
MCN1 release of CabTRP-Ia and proctolin predominantly excites
the pyloric rhythm (Nusbaum et al., 2017).
Mollusks
A few mollusks have been investigated with respect to TK
distribution (using antiserum to locust TK). These include the
pond snail Lymnaea stagnalis, the pulmonate terrestrial snail
Helix pomatia and the freshwater bivalve, Anodonta cygnea
(Elekes and Nässel, 1994;Elekes et al., 1995). In L. stagnalis,
about 180 TK neurons were found, distributed in cerebral and
pedal ganglia and TK axons were detected in the intestine (Elekes
et al., 1995). About 900 TK neurons were seen in H. pomatia
with about 80% of these in cerebral ganglia, whereas in A. cygnea
only a smaller number of TK neurons was detected in cerebral,
pedal and visceral ganglia (Elekes and Nässel, 1994;Elekes
et al., 1995). In the snails, a large number of TK neurons are
located in procerebrum of the cerebral ganglia (Supplementary
Figure S5). The procerebrum is an association center for
olfactory information similar to the mushroom bodies of insects
and thus TKs seem to be involved in olfactory processing also
in mollusks (Elekes and Nässel, 1994). Recently, a TK receptor
related to the Drosophila DTKR and responding to endogenous
TKs was identified in the bivalve mollusk Crassostrea gigas
(Dubos et al., 2018). In the snail Helix, the neuronal membrane
effects of locust LomTK-I, and anodontatachykinin, were either
depolarizing or hyperpolarizing depending on neuron-type, and
voltage-clamp experiments revealed a role of Ca- or K-currents
in these peptide effects (Elekes et al., 1995).
Nematode Worms
In Caenorhabditis elegans, the gene FLP-7 was considered to
encode a TK precursor ortholog (Palamiuc et al., 2017). However,
as mentioned in section “TKs and Their Receptors in Insects and
Other Protostome Invertebrates,” this gene encodes FMRFamide-
like peptides (Mertens et al., 2006) and the proposed receptor
gene (NPR-22) is only remotely related to TK receptors, and more
closely related to the RYamide/Luqin receptor (Ohno et al., 2017;
Yañez-Guerra et al., 2018; see Figure 6). Nevertheless, since the
signaling system was referred to as a TK system (Palamiuc et al.,
2017) we summarize the findings here. It was shown that FLP-
7 is expressed in several tissues, including the head, the nervous
system, and the sensillum (wormbase.org). At the cellular level,
a fluorescent transgenic reporter line revealed that FLP-7 is
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expressed in the ALA motor- and the AVG interneurons and in
the ASI sensory neurons, and that the reporter is secreted into the
“circulation” (Palamiuc et al., 2017). The ALA motor neuron has
been shown to regulate locomotion, the AVG neuron influences
ventral cord development, and the ASI sensory neuron pair
regulates whole body physiology during development, controls
lifespan via neurohormones, and regulates 5-HT-induced fat loss
(Palamiuc et al., 2017). FLP-7 was shown to act in the intestine
to induce lipase activity and fat loss (Palamiuc et al., 2017).
In another study, the ligands of NPR-22 were found to be the
luqin-like peptides LURY-1 and 2 (AVLPRYa and PALLSRYa)
encoded on the gene Y75B8A.11 (Ohno et al., 2017). The LURY
peptides are secreted from pharyngeal neurons and regulate
feeding, lifespan, egg-laying and locomotor activity (Ohno et al.,
2017). In summary, no clear-cut TK signaling system has been
discovered in C. elegans so far.
Ambulacraria
Tachykinin expression has not been mapped yet in echinoderms
or hemichordates.
Functional Roles of TKs in Drosophila,
Genetic Advances
With the introduction of the binary Gal4-UAS system (Brand
and Perrimon, 1993) it became possible to genetically target
components of the TK signaling system spatially and temporarily,
and thus knock down or increase activity in a neuron-
specific fashion. Table 2 summarizes the known functions
of TKs in Drosophila. A first study, utilized Tk-RNAi to
broadly knock down TK production in neurons by means of
ubiquitously expressed drivers (Elav- and tubulin-Gal4) and
monitor effects on olfaction and locomotion (Winther et al.,
2006). The flies with globally reduced TK signaling displayed
decreased responses to certain odors and were hyperactive in
locomotor assays. Subsequent studies describe more targeted
manipulations where TK functions in smaller populations of
neurons could be revealed.
It was found that the TK receptor DTKR is expressed by
olfactory sensory neurons (OSNs) of the Drosophila antennae
and TK in subpopulations of the local neurons (LNs) of the
antennal lobe (Ignell et al., 2009). TK signaling from LNs to
OSNs provides presynaptic inhibitory feedback by suppressing
calcium and synaptic activity (Ignell et al., 2009). An ensuing
study revealed further details on the role of TK signaling in
olfaction and food search (Ko et al., 2015). It was shown
that in hungry flies where circulating levels of insulin-like
peptide (ILP) are low there is an upregulation of the DTKR in
OSNs carrying specific odorant receptors (Or42b and Or85a)
(Figure 9). In the antennal glomerulus DM5, which conveys food
odor aversion (negative valence), upregulation of the inhibitory
DTKR in a hungry fly leads to increased TK signaling and
thus suppressed depolarization and as a consequence decreased
synaptic activation of antennal lobe projection neurons (PNs)
leading to increased food attraction (Ko et al., 2015). When the
fly has fed, and circulating insulin is high, the DTKR expression
decreases due to activation of the insulin receptor in OSNs,
synaptic signaling increase and food aversion is augmented
TABLE 2 | Functions of TKs in Drosophila.
Neurons targeted1Functional TK role indicated References
Global Tk-RNAi Modulation of odor sensitivity Winther et al., 2006
Global Tk-RNAi Modulation locomotor activity Winther et al., 2006
OSNs in AL (Dtkr) Presynaptic inhibitory feedback
to OSNs
Ignell et al., 2009
OSNs in AL (Dtkr) Starvation-induced increase in
odor sensitivity
Ko et al., 2015
Neurons in SEZ (Tk) Modulation of pheromone
response (via Gr68a)
Shankar et al.,
2015
Central complex (Tk) Modulation of explorative
walking
Kahsai et al., 2010a
Brain neurons (Tk) Modulation of aggression level
(fruitless neurons)
Asahina et al., 2014
IPCs (Dtkr) Regulation of insulin production Birse et al., 2011
Nociceptive cells (Dtkr) Modulation of nociception in
sensory cells
Im et al., 2015
ITPn (brain NSCs; Tk) Regulation of metabolic stress
responses
Kahsai et al., 2010a
ICNs (brain neurons)2Inhibit larval IPCs, affect growth
via IIS and EGF
Meschi et al., 2019
Endocrines in gut (Tk) Regulation of lipid metabolism
in intestine
Song et al., 2014
TK endocrines in gut3IMD-mediated DILP
upregulation; organismal
growth
Kamareddine et al.,
2018
In vitro TK application Induces midgut contraction Siviter et al., 2000
In vitro TK application Modulation of heart contraction
rate
Schiemann et al.,
2018
1In brackets: genetic interference with peptide (Tk) or receptor (Dtkr). 2Ablation
of TK-expressing ICN neurons, activation or inactivation of neurons. 3Interference
with signaling in TK expressing endocrines. OSN, olfactory sensory neurons;
AL, antennal lobe; SEZ, subesophageal zone; IPC, insulin-producing cells; ITPn,
ITP neurons; NSC, neurosecretory cell; ICN, IPC contacting neurons; EGF,
epidermal growth factor; IMD, immune-deficiency pathway; DILP, Drosophila
insulin-like peptide.
(Figure 9). In glomerulus DM1 (positive valence; wired for food
odor attraction) innervated by Or42b expressing OSNs, enhanced
signaling with sNPF increases food attraction in hungry flies with
low circulating insulin (Ko et al., 2015). This enhanced signaling
is caused by up-regulation of sNPF receptor expression on OSNs
and strengthened synaptic activation of PNs (Figure 9). Together,
peptidergic neuromodulation of the two odor channels (DM1 and
DM5) ensures that hungry flies increase food search. Whereas
it has been shown that sNPF facilitates cholinergic transmission
in OSNs to PNs (Ko et al., 2015), it is not clear whether TK
acts to modulate inhibitory GABA transmission in LNs (Ignell
et al., 2009). Also in the cockroach Periplaneta americana (Jung
et al., 2013) and the oriental fruitfly Bactrocera dorsalis (Gui
et al., 2017b), TK signaling modulates olfactory sensitivity, and
the presence of TK in antennal lobe neurons in all studied insects
may suggest a conserved role in olfaction.
In the central complex of Drosophila, TK is found in a
few sets of neurons (light red neurons in Figure 8A) and in
assays of explorative walking TK knockdown in some of these
neurons resulted in flies with increased center zone avoidance,
whereas knockdown in other neurons resulted in flies with
increased activity-rest bouts (Kahsai et al., 2010b). Thus, TK in
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the central complex seems to be important for modulation of
spatial orientation, activity levels, and temporal organization of
spontaneous walking.
A small set of protocerebral TK neurons (light blue in
Figure 8A) have been shown to regulate levels of aggression in
male Drosophila (Asahina et al., 2014). These TK neurons are
a small subpopulation of the numerous neurons that express
the male splice form of fruitless (FruM+), a transcription factor
that specifies male-specific behavior, including male aggression.
Thus, a set of 4 pairs of neurons in the brain designated Tk-
GAL4FruM neurons control the level of male-male aggression,
but have no influence on male-female courtship behavior
(Asahina et al., 2014). The same authors found that the Tk-
GAL4FruM neurons also may be cholinergic (express marker for
acetylcholine signaling) and that this neurotransmitter may thus
play an additional role in the circuit.
Another male-specific TK circuit in Drosophila is involved in
gustatory detection of an anti-aphrodisiac pheromone (CH503).
Gustatory cells (Gr68a) in the forelegs respond to this pheromone
and mediate signals to central brain circuits via 8 to 10 TK
neurons located in the subesophageal zone and thereby suppress
courtship (Shankar et al., 2015). It is not clear from this study to
which specific neurons TK in Figure 8 they correspond.
The insulin-producing cells (IPCs) of the Drosophila brain are
modulated by several factors, including TK (Birse et al., 2011;
Nässel and Vanden Broeck, 2016). The IPCs produce four insulin-
like peptides (DILP1, 2, 3, and 5) and are known to regulate
many aspects of development and adult physiology, such as
growth, metabolism, stress responses, reproduction and lifespan
reviewed in Owusu-Ansah and Perrimon (2014),Nässel and
Vanden Broeck (2016). Knockdown of the receptor DTKR in
IPCs affected levels of dilp2 and dilp3 transcripts in these cells,
increased the fly lifespan and diminished carbohydrate levels
during starvation (Birse et al., 2011). Knockdown of the natalisin
receptor (NTLR; CG6115; earlier known as NKD) had no effect
on IPC activity and the TK cells acting on the IPCs were not
identified (Birse et al., 2011). In a more recent paper, a pair of
TK neurons was demonstrated in the Drosophila larva, which
connect functionally to the IPCs (Meschi et al., 2019). These
TK neurons (ICNs) are inhibitory on IPCs. Under protein-rich
diet conditions the ICNs respond to growth-blocking peptides
secreted from the larval fat body and this alleviates the inhibitory
action on IPCs, and DILPs can be released to stimulate growth
(Meschi et al., 2019). It is not completely clear from the images
of this paper, but it appears as if the ICNs are the same as the
descending neurons shown in Figure 8C (blue arrows), which
also exist in the adults (DN in Figure 8A).
In larvae, a nociceptive pathway mediating thermal tissue
damage signals was identified and shown to include TK and
the receptor DTKR (Im et al., 2015). The DTKR receptor is
expressed in the nociceptive sensory neurons and required for
mediation of thermal hypersensitivity after tissue damage. A set
of TK expressing interneurons in the ventral nerve cord mediates
this presynaptic modulation of nociceptive sensory neurons (Im
et al., 2015). Substance P is known for its role in modulation of
nociceptive sensory signals in the dorsal horn of the spinal cord
[see (Hökfelt et al., 2001;Steinhoff et al., 2014)], suggesting a
conserved role of tachykinin signaling, although the pathway and
mechanisms differ.
A set of five pairs of large neurosecretory cells (ITPn in
Figure 8A) produces TK, as well as ITP and sNPF. Targeted
knockdown of TK (or sNPF) in these cells result in flies that
display decreased survival time when exposed to desiccation or
starvation, and also suffer increased water loss at desiccation
(Kahsai et al., 2010a). ITP is acting as an antidiuretic hormone
(Galikova et al., 2018), but it is not likely that TK or sNPF are
released as circulating hormones from the ITPn cells (Kahsai
et al., 2010a). Instead, these peptides might act locally, either
presynaptically on ITPn axon terminations, or on other brain
neurons/neurosecretory cells to modulate antidiuretic signals
or metabolic stress responses. A similar local action of sNPF
released from lateral neurosecretory cells in the brain has been
demonstrated; it was found that the IPCs in the brain and the
AKH-producing cells in the CC were directly regulated by locally
released sNPF (Kapan et al., 2012;Oh et al., 2019).
In gut endocrine cells (EECs) of Drosophila, TK was shown
to influence lipid homeostasis by controlling lipid production
in enterocytes of the midgut (Song et al., 2014). These TK-
(and DH31-) producing EECs are nutrient-sensing and can
be activated by the presence of circulating dietary proteins
and amino acids (Park et al., 2016). The EECs have also
been shown to play a role in the innate immune system
and development of Drosophila (Kamareddine et al., 2018).
Activating the immune deficiency (IMD) pathway in EECs
triggers TK signaling leading to DILP3 upregulation in the
gut and mobilization of lipids increased insulin signaling and
effects on organismal development and growth. Thus, the gut
microbiota can influence growth via the immune system and TK
and insulin signaling (Kamareddine et al., 2018). TK was also
shown to activate peristalsis in the midgut (Siviter et al., 2000),
maybe by local paracrine signaling.
Functional Roles of TKs in
Protochordates and Non-mammalian
Vertebrates
Also in several non-insect invertebrates and non-mammalian
vertebrates TKs were found to exhibit contractile activity on
muscles in the digestive tract (Satake and Kawada, 2006;Satake
et al., 2013;Steinhoff et al., 2014). In the following we will
discuss additional roles of TKs in sea squirts (Ascidians) and fish,
exemplified by Zebrafish.
Ascidians
Aoyama et al. (2012) demonstrated that CiTK induces growth
of follicles in Ciona during late stage-II (vitellogenic stage)
to stage-III (post-vitellogenic stage) via up-regulation of gene
expression and the enzymatic activities of follicle-processing
proteases: cathepsin D, chymotrypsin, and carboxypeptidase B1.
This is consistent with the finding that CiTKR is expressed
exclusively in test cells (functional counterparts of vertebrate
granulosa cells) residing in late stage-II follicles (Aoyama et al.,
2012). Moreover, Ci Cathepsin D, co-localized with CiTKR in
test cells, is initially activated, and Ci Carboxypeptidase B1 and
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Ci Chymotrypsin, localized in follicular cells, are activated 1 h
later (Aoyama et al., 2012). These findings provide evidence
for a novel tachykininergic follicle growth pathway. In addition,
the CiTK-induced follicle growth is suppressed by a Ciona-
specific neuropeptide, CiNTLP6, via downregulation of the three
aforementioned proteases (Kawada et al., 2011). It would be
interesting to reveal whether the tachykininergic regulation of
follicle growth is conserved, at least in part, in vertebrates or
other invertebrates.
Teleost Fish
The roles of NKB in reproductive functions are of interest in both
teleosts and mammals. NKB is expressed in the hypothalamus
of mammals (Satake and Kawada, 2006;Steinhoff et al., 2014).
Moreover, NKB is colocalized with kisspeptin and dynorphin
A in KNDy neurons in the arcuate nuclei. KNDy neurons and
NKB are responsible for the generation of GnRH pulsatility in
the hypothalamus, which plays a central role in reproductive
functions via induction of secretion of gonadotropins (LH and
FSH) from the pituitary to the gonads (Lehman et al., 2010;
Navarro, 2012). Interestingly, some mutations were detected in
the genomic sequences of human Tac3 and Tacr3 in a portion
of patients with hypogonadotrophic hypogonadism (Topaloglu
et al., 2009;Chen et al., 2018). NKB is likely to downregulate
production of LH and FSH in zebrafish, tilapia and goldfish
(Biran et al., 2012;Qi et al., 2015;Hu et al., 2017;Chen et al., 2018;
Liu et al., 2019). Several of these studies also indicated that NKB
and/or NKF (identical to NKB-related peptide) downregulate
the expression of kiss2 that is a homolog of mammalian
kisspeptin. The role of mammalian kisspeptin in induction of
GnRH synthesis and release may suggest that kisspeptin 2 also
upregulates GnRH synthesis and release in teleost. However,
conservation of such kisspeptin 2-directed GnRH regulation in
teleost is not likely, since kisspeptin 2 seems not to be involved
in reproduction in teleosts (Nakajo et al., 2017). Collectively,
these findings suggest that biological roles of NKB and NKF in
reproduction in teleost are distinct from those in mammals. In
addition, SP and NKA were found to upregulate gene expression
and release of LH, prolactin, and somatolactin αin carp pituitary
cells (Hu et al., 2017). Interestingly, short-term SP treatment (3 h)
induces LH release, but long-term SP treatment attenuated gene
LH expression (Hu et al., 2017). Thus, in teleosts SP and NKA are
important in reproductive functions.
CONSERVED ROLES OF TACHYKININ
SIGNALING IN THE ANIMAL KINGDOM
Some of the functional roles of TKs that have been described
in some detail in earlier sections are evolutionarily conserved,
at least in general terms. By general terms we mean that for
instance a role in nociception has been found for TKs both in
Drosophila (Im et al., 2015) and in mammals [see (Onaga, 2014;
Steinhoff et al., 2014;Zieglgänsberger, 2019)], but the neuronal
pathways and mechanisms are quite different. In a similar
fashion, TKs are acting as cotransmitters in many neuronal
circuits and thus play roles in for instance: modulation of
olfactory sensory signaling together with GABA in Drosophila
(Ignell et al., 2009;Ko et al., 2015) and mammals (Olpe et al.,
1987), modulation of rhythm generating motor networks in
crustaceans (Nusbaum et al., 2017) and lampreys (Parker and
Grillner, 1998), aggression in Drosophila (Asahina et al., 2014)
and mammals (Felipe et al., 1998;Katsouni et al., 2009), as well as
roles in learning and memory circuits in honey bees (Takeuchi
et al., 2004;Brockmann et al., 2009;Boerjan et al., 2010) and
mammals (Lénárd et al., 2018). Furthermore, TKs are involved
in regulation of several aspects of intestinal function, including
electrolyte and fluid secretion in insects (Johard et al., 2003;
Veenstra et al., 2008;Lemaitre and Miguel-Aliaga, 2013;Song
et al., 2014) and mammals (Hökfelt et al., 2001;Steinhoff et al.,
2014), in regulation of gustatory receptors in Drosophila (Shankar
et al., 2015) and mammals (Onaga, 2014) and in control of
hormone release in insects (Nässel et al., 1995b;Birse et al., 2011;
Meschi et al., 2019) and vertebrates (Hu et al., 2014;Steinhoff
et al., 2014;Zhang et al., 2019).
Roles of TKs in reproductive functions have been
demonstrated in vertebrates (Satake et al., 2013;Steinhoff
et al., 2014), but not yet in insects or other invertebrates.
However, in insects and other arthropods natalisins seem to
be important in reproductive behavior, as outlined in the next
section (Jiang et al., 2013;Gui et al., 2018).
NATALISINS, A SISTER GROUP OF
TACHYKININS IN ARTHROPODS
A novel peptide precursor gene that encodes multiple copies of
peptides that were designated natalisins (NTLs) was discovered
in Drosophila,Tribolium castaneum, and Bombyx mori; these
have a consensus sequence FXXXRamide (Jiang et al., 2013). The
name NTL is derived from the functional role of the peptide in
reproduction (Latin word natalis for birth) (Jiang et al., 2013).
The NTLs have so far only been identified in arthropods and
tardigrades, and the peptides display minor similarities to TKs.
However, the NTL receptor (NTLR) was previously identified as
a TK receptor (CG6115; TakR86C; NKD) (Monnier et al., 1992;
Poels et al., 2009), suggesting that NTLs are ancestrally related to
arthropod TKs (Jiang et al., 2013). In fact, phylogenetic analysis
suggests that NTL signaling arose through duplication of the TK
signaling early in the arthropod lineage (Jiang et al., 2013; see
Figure 6). However, TK-like precursors with NTL-like peptides
are found in the spider mite (chelicerate) as well as tardigrades as
shown in Figures 4,5, suggesting that the NTL signaling might
also be present outside arthropods (Veenstra et al., 2012;Koziol,
2018). It was noted that in the centipede Strigamia maritima
(Myriapoda) there is no NTL gene (Veenstra, 2016) and in the
spider mite Tetranychus urticae, there is no separate NTL gene
in the genome (Veenstra et al., 2012). However, two TK genes
were annotated in T. urticae and on these precursors two of the
three putative mature peptides are similar to NTL, and one is
a TK; the second precursor encodes two TKs and an unrelated
peptide, but no NTL (Figure 4). Thus, with this mix of TKs
and NTLs on the spider mite genes, it was suggested that TK
and NTL divergence started by internal events on duplicated TK
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genes and resulted in the evolution of a separate NTL signaling
system (Jiang et al., 2013). Additional genomes/transcriptomes of
basal arthropods need to be examined to substantiate this claim.
As seen in Supplementary Table S5, there are five paracopies of
natalisins in Drosophila, 7 in Anopheles aegypti, 11 in Bombyx
mori and 15 in Manduca sexta, 2 in Tibolium castaneum and only
one each in the tardigrades Hypsibius dujardini and Ramazzottius
varieornatus (Jiang et al., 2013;Koziol, 2018). The Drosophila
peptides (DmNTL1-5) range from 15 to 24 residues and have a
consensus C-terminus FXPXRamide (except DmNTL4).
In the brains of Drosophila, B. mori, T. castaneum and Varroa
destructor, there are two pairs of identifiable NTL neurons
with very similar locations and arborizations (designated ADLI
and ICLI in each species) (Jiang et al., 2013, 2016). The
Drosophila neurons are shown in Supplementary Figure S6. In
the B. mori brain, there are two additional pairs of neurons in
the subesophageal zone. Another study shows that in the oriental
fruit fly Bactrocera dorsalis there are three pairs of NTL neurons
(Gui et al., 2017a). Thus, in insects studied so far, the NTL system
appears relatively simple and the neuronal branches do not seem
to innervate any of the well-defined centers, such as antennal
lobes, mushroom bodies, central complex or optic lobes (Jiang
et al., 2013). There are a few additional segmental neurons in the
ventral nerve cord. The brain ICLI neurons coexpress NTL, Ast-A
and MIP (Diesner et al., 2018).
In Drosophila, genetic experiments revealed that NTL and
the four NTL neurons are important for male mating success
(Jiang et al., 2013). NTL-RNAi in NTL-Gal4 neurons reduces
male copulation success rate. The courtship behavior was only
affected in the latency of courtship initiation in males. NTL-RNAi
females also displayed reduced mating frequency, but did not
actively reject males (Jiang et al., 2013). Silencing of the NTL-
Gal4 neurons resulted in complete repression of mating in males,
but had no effect in females. Manipulations of NTL neurons had
no effect on egg laying, however, in T. castaneum systemic NTL-
RNAi in either sex resulted in reduced egg numbers after mating
(Jiang et al., 2013). Also in the oriental fruit fly Bactrocera dorsalis
NTL and its receptor (NTLR) play important roles in mating (Gui
et al., 2017a, 2018). In this species the NTL signaling is required
for regulation of mating frequency in both males and females.
CONCLUSION AND PERSPECTIVES
We have shown that TKs are neuropeptides that emerged early
in bilaterian lineages, but it is not clear what their ancestral
form is since cnidarians and other non-bilaterian do not possess
typical TKs, although bioinformatics has indicated presence of
TK receptors [see (Krishnan and Schiöth, 2015;Hayakawa et al.,
2019)]. It is also puzzling that no typical TKs have been identified
in echinoderms, acorn worms, or amphioxus. Possibly this is
due to species-specific diversification of TK sequences. Thus,
important questions regarding the evolution and diversification
of this signaling system remain unanswered. Nevertheless, it
is clear that TK signaling is widespread and diverse among
bilaterians and contributes to many vital functions. Some of
these functions appear conserved over evolution, at least in
general terms. It is important to stress that TKs seem to have
multiple distributed (localized) functions in different neuronal
circuits and commonly act as co-transmitters, and thus TK
signaling is not likely to orchestrate global functions. Elucidation
of TK functions in neglected phyla (such as echinoderms,
xenacoelomorphs and cnidarians) can also provide clues on
whether the mode of action of TK as a co-transmitter is an
ancient or a more derived trait. This is important since besides
TK, there are only a few other neuropeptides in protostomes
(at least in arthropods) that seem to function mainly as co-
transmitters, such as sNPF and proctolin (Nässel, 2018;Nässel
and Zandawala, 2019). Did TKs evolve as primary paracrine
peptide signals in basal phyla with simple nervous systems, and
then diversified functionally to also confer plasticity to more
complex neural circuits by providing neuromodulatory actions
as co-transmitters? In organisms without nervous systems, such a
Trichoplax adherens, peptides seem to act as primary messengers
that induce simple behaviors (Nikitin, 2015;Senatore et al., 2017;
Varoqueaux et al., 2018) and even in more evolved organisms
many neuropeptides/peptide hormones seem to relay single
global orchestrating actions [see (Nässel and Zandawala, 2019;
Nässel et al., 2019)].
In mammals, TK signaling has received extensive attention
due to its clinical importance with roles for instance in pain,
inflammation, cancer, depressive disorder and immune system.
Thus, the literature list is huge: searching PubMed for the term
“substance P” renders more than 24,000 hits. This means that
our coverage of mammalian TKs in this review is very superficial
and incomplete. On the other hand, a search for e.g., “tachykinin
in insects” yields about 200 hits and therefore our discussion
of invertebrate TKs is somewhat more detailed, but certainly
still providing a sketchy picture of TK signaling since functional
studies are not yet that numerous.
The development of powerful genetic tools, not only in
Drosophila and C. elegans, but also other organisms has improved
the possibilities to analyze neuropeptide signaling down to
single identified neurons or sets of neurons. Furthermore,
with optogenetics and other strategies for temporal control of
manipulations and elegant techniques for imaging neuronal
connections or activity, we already see an increase in studies
of invertebrate neuropeptides. For TKs, it is of importance to
note that in the CNS these peptides seem to operate as local
neuromodulators and/or co-transmitters. Many (if not most) TK
expressing neurons may additionally signal with small molecule
transmitters and, therefore, manipulations of TK signaling only
remove one layer of the signal transfer.
Whereas many neuropeptides also have functions as
circulating hormones [see (Nässel and Zandawala, 2019)], it
seems like TKs do not in most organisms studied. In studies
of cockroach, locust and Drosophila it was proposed that TKs
are released into the circulation from gut endocrine cells to
stimulate secretion in nearby Malpighian tubules (Winther and
Nässel, 2001;Johard et al., 2003;Söderberg et al., 2011). A recent
Drosophila study showed that gut TKs act locally and do not
affect behavior, indicating that there is no signaling to the brain
via the circulation (Song et al., 2014). If bona fide hormonal
roles of TKs can be excluded, we can focus on their local actions,
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Nässel et al. Tachykinins: Ancient Multifunctional Neuropeptides
but we still face some difficulties due to the diversity of TK
expressing neuronal systems and the co-expression of small
molecule transmitters. Hopefully this review will trigger interest
in TK signaling in invertebrates in spite of these challenges. It
is obvious from the literature that research on TK signaling in
mammals is already very extensive, but certainly further basic
research and clinical studies are urgently needed to unravel this
important and interesting signaling system.
AUTHOR CONTRIBUTIONS
DN contributed to the conceptualization, prepared the first draft
of the manuscript, wrote parts of the manuscript, prepared figures
and tables, and coordinated the assembly of the manuscript.
MZ contributed to the conceptualization, wrote parts of the
manuscript, and prepared figures and tables. TK and HS wrote
parts of the manuscript, and prepared figures and tables. All
authors edited and finally approved the manuscript.
FUNDING
This work was funded by the Swedish Research Council
(Vetenskapsrådet), grant number 2015-04626 (DN) and the
Japan Society for the Promotion of Science, grant number
JP19K06752 (HS).
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fnins.
2019.01262/full#supplementary-material
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