The family of K2P channels: Salient structural and functional properties

Abstract

K+ channels participate in many biological functions from ion homeostasis to generation and modulation of the electrical membrane potential. They are involved in a large variety of diseases. In the human genome, 15 genes code for K+ channels with two pore-domains (K2P). These channels form dimers of pore-forming subunits that produce background conductances finely regulated by a range of natural and chemical effectors, including signaling lipids, temperature, pressure, pH, antidepressants and volatile anesthetics. Since the cloning of TWIK1, the prototypical member of this family, a lot of work has been carried out about their structure and biology. These studies are still in progress, but data gathered so far show that K2P channels are central players in many processes including ion homeostasis, hormone secretion, cell development and excitability. A growing number of studies underline their implication in physiopathological mechanisms such as vascular and pulmonary hypertension, cardiac arrhythmias, nociception, neuroprotection and depression. This review gives a synthetic view of the most noticeable features of these channels.This article is protected by copyright. All rights reserved

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This article is protected by copyright. All rights reserved. 1
The family of K2P channels: salient structural and functional properties
Sylvain Feliciangeli1, Frank C. Chatelain1, Delphine Bichet1 and Florian Lesage1,2
1LabEx ICST, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS and Université de
Nice-Sophia Antipolis, 660 Route des Lucioles, 06560 Valbonne, France
2to whom correspondance should be addressed: lesage@ipmc.cnrs.fr
“This article is an invited review for the NIPS-J Physiol Symposium”
Abstract
K+ channels participate in many biological functions from ion homeostasis to generation
and modulation of the electrical membrane potential. They are involved in a large variety
of diseases. In the human genome, 15 genes code for K+ channels with two pore-domains
(K2P). These channels form dimers of pore-forming subunits that produce background
conductances finely regulated by a range of natural and chemical effectors, including
signaling lipids, temperature, pressure, pH, antidepressants and volatile anesthetics.
Since the cloning of TWIK1, the prototypical member of this family, a lot of work has
been carried out about their structure and biology. These studies are still in progress, but
data gathered so far show that K2P channels are central players in many processes
including ion homeostasis, hormone secretion, cell development and excitability. A
growing number of studies underline their implication in physiopathological
mechanisms such as vascular and pulmonary hypertension, cardiac arrhythmias,
nociception, neuroprotection and depression. This review gives a synthetic view of the
most noticeable features of these channels.
Abbreviations: AA, arachidonic acid; ER, endoplasmic reticulum; K2P, 2-pore domain potassium
channel; LP, lysophospholipids; PKA, protein kinase A; PKC protein kinase C; PLD2,
phospholipase D2; PUFA, poly-unsaturated fatty acids.

This article is protected by copyright. All rights reserved. 2
K+ channels are important for K+ transport and cell volume regulation. By modulating the
electrical membrane potential they are also necessary for functions as diverse as
neurotransmission, neuronal coding of information, heart beating, muscle contraction and
hormone secretion. With more than 78 genes encoding pore-forming subunits in the human
genome, K+ channels form the largest ion channel family. It comprises three different structural
subclasses related to voltage-gated K+ (Kv) channels, inward rectifiers (Kir) and two-pore domain
K+ (K2P) channels (Goldstein et al. 2005; Gutman et al. 2005; Kubo et al. 2005; Wei et al. 2005;
González et al. 2012). Whereas the prototypical members of the Kv and Kir subclasses were
cloned on purpose using genetics and/or expression cloning, K2P channels were identified by
DNA database mining without clues about the electrophysiological and functional properties of
their native correlates (Lesage et al. 1996a). In heterologous systems, they were found to produce
currents similar to native currents previously identified in cardiac and neuronal cells, including
background K+ currents, arachidonic acid (AA)-activated K+ current and mechano-gated K+
currents (for examples Franks & Lieb, 1988; Premkumar et al. 1990; Sackin, 1995; Kim et al.
1995). 15 genes (noted KCNKx) encode K2P channel pore-forming subunits. Alternative splicing
and translation initiation, heteromerization and post-translational modifications further increase
this diversity. These channels are regulated by a wide range of physical and chemical stimuli, and
are the targets of drugs including anesthetics as well as neuroprotective and antidepressive agents.
K2P channels are involved in the development and excitability of many cell types. The
characterization of their physiological and pathological functions is still ongoing, mainly using
animal models. The scope of this review is to provide a synthetic overview of the most salient
features of these channels. For in-depth information, the reader is referred to several exhaustive
reviews such as (Enyedi & Czirják, 2010; Mathie et al. 2010; Noël et al. 2011; Lesage & Barhanin,
2011).
Structural features of the K2P channels
K+ channels contain a short signature sequence called the pore (P) domain. The assembly
of four P domains forms the selectivity filter of an active channel (Doyle et al. 1998). All the
subunits directly related to Kv and Kir channels contain a single P domain and assemble as
tetramers. TWIK1, the prototypical member of the K2P channel class, was found by identifying a
non-conventional P domain in an expressed sequence tag from human kidney (Lesage et al.
1996a). Cloning and sequencing of the corresponding full-length cDNA revealed the presence of
two P domains (P1 and P2) while biochemical experiments showed that TWIK1 was able to
form dimers containing 4 P domains, each P domain being flanked by two membrane-spanning
helices (M1, M2, M3 and M4, respectively, Figure 1A). N- and C-termini of TWIK1 are
cytoplasmic. Another unique feature is the presence of an extended extracellular loop between
domains M1 and P1. This M1P1 loop is a coiled-coiled domain that interacts with the same
structure of the other subunit of the dimer (Lesage et al. 1996b). It contains a cysteine residue
(cys 69) involved in the formation of a covalent bridge between two subunits (Lesage et al.
1996b). Purification and crystallization of TWIK1 (Miller & Long, 2012) and of the related
TRAAK channel (Brohawn et al. 2012) have confirmed this organization, showing that the P
domains are organized with a pseudo four-fold symmetry (Figure 1B). Both structures also
showed that the M1P1 loop is highly structured into a helical cap that provides an ion pathway in
which K+ ions flow through side portals. Disulfide-bridged cysteines are at the top of the cap
and stabilize the structure. The crystals also revealed the existence of fenestrations that expose
the inner pore of the channel to the lipid bilayer.
By sequence homology, 14 subunits related to TWIK1 were cloned that display the same
overall organization. Based on sequence conservation and functional properties, these subunits
were classified into six groups: TWIK for Two P-domain in a weakly inward rectifying K+
channel, TREK (TWIK-related K+ channel), TASK (TWIK-related acid sensitive K+ channel),
TALK (TWIK-related alkaline sensitive K+ channel), THIK (Tandem pore domain halotane-

This article is protected by copyright. All rights reserved. 3
inhibited K+ channel), and TRESK (TWIK-related spinal cord K+ channel) (Figure 1C). The
only noticeable variations in the structural organization are the absence of a disulfide bond in the
caps of TASK1 and TASK3 dimers and the presence of a long intracellular M2M3 loop in
TRESK (Enyedi et al. 2012). Whereas regulations by the cellular machinery involve the C-ter of
many K2P channels, known regulations of TRESK take place in this M2M3 loop. Usually, a
KCNK gene produces a unique K2P subunit. However the TREK/ TRAAK subclass exhibits
additional subunit diversity. Alternative transcription initiation leads to the production of
TREK1 and TREK2 variants with shortened cytoplasmic N-ter, associated with a change of
ionic selectivity for TREK1 (Thomas et al. 2008), and a change of unitary conductance for
TREK2 (Simkin et al. 2008). In addition, alternative exon splicing produces variants of TREK1,
TREK2 and TRAAK with variable levels of activity (Fink et al. 1996; Lesage et al. 2000a, 2000b;
Gu et al. 2002; Ozaita & Vega-Saenz de Miera, 2002; Veale et al. 2010; Rinné et al. 2014). Tissue-
specific expression of some variants and dominant-negative effect of one of them suggest that
alternative splicing may be involved in the functional regulation of TREK/TRAAK channels.
Electrophysiological properties of K2P channels
Unlike Kv channels, K2P channels have no voltage-sensor and are not gated by the
membrane potential (Lesage et al. 1996a; Fink et al. 1996; Duprat et al. 1997). Many of them
produce almost instantaneous and non-inactivating currents on the whole range of the
membrane potential. These properties mark them as background or leak K+ channels, predicted
to follow the Goldman-Hodgkin-Katz current equation for a K+-selective leak current. If
TASK1 currents follow perfectly this equation (Duprat et al. 1997), others exhibit some
variations such as a slight outward (TREK1) (Bockenhauer et al. 2001; Fink et al. 1996) or inward
(TWIK1, TWIK2) rectification (Lesage et al. 1996a; Patel et al. 2000). Other unusual features are
observed such as a slow inactivating component that represents about 50% of the TWIK2
current (Patel et al. 2000), different subconductance states for TREK1 and TREK2 (Fink et al.
1996; Patel et al. 1998; Lesage et al. 2000b; Kang et al. 2007; Simkin et al. 2008) and an
asymmetrical gating behavior for TRESK (Czirják et al. 2004). Regardless of these differences,
K2P channels are all insensitive or very weakly sensitive to the classical K+ channel blockers such
as tetraethyl ammonium (TEA), Ba2+, Cs+ and 4-aminopyridine (4-AP). This lack of specific
pharmacology as well as their time- and voltage-independences explains why these currents have
been overlooked despite their presence in many tissues and cells. However, even if these
channels behave as leaks, they are finely regulated by many different stimuli (Table 1) and these
regulations have proven to be really useful to correlate cloned and native channels.
Recent observations suggest that the gating mechanism in K2P channels may be different
from those of other K+ channels. In Kir and Kv channels, modulation of the activity occurs via
the opening/closure of two distinct gates. The upper (or outer) gate takes place at the selectivity
filter whereas the lower (or inner) gate comprises the lower part of the inner membrane-
spanning helices. Functional studies and crystal structure suggest that the access to the inner
pore cavity is not modified by different stimuli that regulate K2P channel activity, leading to a
model in which the primary activation mechanisms reside close to, or within the selectivity filter
and do not involve gating at the lower cytoplasmic bundle crossing (Bagriantsev et al. 2011, 2012;
Brohawn et al. 2012; Miller & Long, 2012; Piechotta et al. 2011).
Regulation of the K2P channels by pH
Except THIK1/2 and TRESK, K2P channels are sensitive to pH. TASK and TALK
channels are inhibited by acidification of the extracellular medium. The pKa value of this
inhibition makes some channels active at neutral pH and inhibited by acid (pKa of 7.3 for
TASK1 and 6.7 for TASK3) (Duprat et al. 1997; Kim et al. 2000; Rajan et al. 2000), and others
active at alkaline pH and less active (TASK2), largely inhibited (TALK1) or totally inhibited
(TALK2) at neutral pH (Reyes et al. 1998; Kang & Kim, 2004). The pH sensor is constituted

This article is protected by copyright. All rights reserved. 4
primarily of a histidine residue in the P1 domains of TASK1 (Morton et al. 2003) and TASK3
(Kim et al. 2000; Rajan et al. 2000), and of a basic residue in the P2M4 loop of the TALKs
(Niemeyer et al. 2006, 2007). In the TREK/TRAAK subfamily, the effect of the pH is more
contrasted. TREK1 and TREK2 channels are activated by internal acidification, whereas
TRAAK is activated by internal alkalinization. External acidification inhibits TREK1 and
TRAAK but activates TREK2 (Duprat et al. 1997; Maingret et al. 1999b; Kim et al. 2001a, 2001b;
Sandoz et al. 2009). The sensor for activation of TREK1 and TREK2, but not TRAAK, by
internal pH is located in their C-ter (Maingret et al. 1999b; Kim et al. 2001b). The sensitivity to
external pH requires a histidine residue in the M1P1 loop (Sandoz et al. 2009). Residues in the
P2M4 loop, negatively charged in TREK1 and positively charged in TREK2, are responsible for
the opposite effect of acidification on these channels, suggesting electrostatic
attraction/repulsion with the protonated side chain of the histidine sensor leading to the opening
or the closure of the pore. TWIK1 also displays a marked sensitivity to extracellular acidification,
but with a very different effect. The channel reversibly shifts from a strict selectivity to K+ at
neutral pH to a state permeable to Na+ at acidic pH, demonstrating that TWIK1 possesses a
dynamic ion selectivity (Chatelain et al. 2012). A low K+ concentration has the same effect (Ma et
al. 2011). This loss of K+ selectivity would cause paradoxical depolarization of human cardiac
cells in pathological hypokaliemic conditions (Chen et al. 2014). Based on these findings it was
also reported that acidification affects the ion selectivity of TASK1 and TASK3 (Ma et al. 2012).
These data show that external parameters can affect ion selectivity of K2P channels. This finding
expands the range of potential roles for K2P channels that may also behave as excitatory channels
when they are permeable to Na+.
Unique regulation of TWIK1
Dynamic ion selectivity of TWIK1 has been reported only very recently, although the
channel has been identified almost two decades ago (Lesage et al. 1996a). This lag was due to the
difficulty to study TWIK1 currents. Indeed, no native currents corresponding to TWIK1 have
been characterized so far, and its weak activity was recorded only in a few heterologous
expression systems. The identification of highly active K2P channels soon after the discovery of
TWIK1 overshadowed its study for a time. Two models were proposed to explain the lack of
TWIK1 expression. In the first model, TWIK1 is present at the plasma membrane but silenced
by the binding of a SUMO polypeptide to a non-conventional SUMO binding site (Rajan et al.
2005). When this site is inactivated by mutagenesis, the corresponding channel produces
measurable currents. Following this line, the authors later reported that TWIK1 heteromerizes
with TASK1/3 subunits and brings sumoylation sensitivity to the TWIK1/TASK heteromeric
complexes (Plant et al. 2012). In the second model, low activity of TWIK1 is explained by its
intracellular localization. The channel is rapidly and constitutively endocytosed from the plasma
membrane and accumulates in recycling endosomes (Decressac et al. 2004; Feliciangeli et al. 2007,
2010). A mutant lacking the endocytosis signal redistributes at the plasma membrane, giving
recordable current. This mutant allowed a reassessment of the electrophysiological properties of
TWIK1 (Chatelain et al. 2012). This work demonstrated that TWIK1 current is increased by
mutations that target the pore of the channel without affecting the putative sumoylation site.
Recent data show the existence of a hydrophobic barrier within the deep inner pore, the
stochastic dewetting of which being a major barrier to ion conduction (Aryal et al. 2014).
Not so silent K2P subunits
Beside TWIK1, other K2P subunits (namely TASK5, KCNK7 and THIK2) have been
coined “silent” subunits because of their lack of expression in heterologous systems (Bichet et al.
2014). This raises the question as to whether they are non-functional isoforms or functional
subunits that require unidentified activators and/or protein partners. This second possibility has
been strengthened by the recent demonstration that THIK2 could be turned on by overcoming

This article is protected by copyright. All rights reserved. 5
two silencing mechanisms, retention in the endoplasmic reticulum and low activity at the plasma
membrane (Chatelain et al. 2013; Renigunta et al. 2014b). Inactivation of the ER retention signal
allowed the expression of THIK2 at the plasma membrane making it possible to carry out its
electrophysiological characterization. THIK2 has electrophysiological and pharmacological
properties very similar to those of THIK1, including inhibition by halothane and insensitivity to
extracellular pH changes. Mutations equivalent to the pore mutations activating TWIK1 were
able to activate THIK2 suggesting that THIK2 also contains a hydrophobic barrier in its deep
pore (Chatelain et al. 2013). These results suggest that a similar approach may be successful to
obtain functional expression of the “silent” TASK5 and KCNK7 K2P subunits.
Homo and heteromerization of K2P subunits
Further studies showed that THIK2 assembles with THIK1 to form an active channel
(Blin et al. 2014). The resulting heterodimer reaches the cell surface and exhibits novel
electrophysiological properties, providing evidence that interaction with another subunit can
modulate K2P channel activity. Whether such a mechanism also apply to silent TASK5 and
KCNK7 subunits remains to be established. THIK1 and THIK2 are not the only K2P subunits
able to form active heterodimers. The best documented case involves TASK1 and TASK3
(Czirják & Enyedi, 2002a; Berg et al. 2004). The resulting heterodimer retains some of the
properties of each monomer and exhibits some others that are intermediate. There is a strong
physiological relevance, since native TASK heterodimers have been reported in different tissues
where they account for a significant part of the leak current (Enyedi & Czirják, 2010). As
mentioned before, TWIK1 may also interact with TASK1 and TASK3 subunits in the
cerebellum (Plant et al. 2012). Recent data show that in astrocytes TWIK1 and TREK1 form
heterodimers that mediate astrocytic passive conductance and cannabinoid-induced glutamate
release (Hwang et al. 2014). This result suggests that TWIK1/TREK1 heterodimers are
permeable to large molecules such as glutamate. However, the molecular mechanisms underlying
this unexpected property are not known yet.
Interacting partners of the K2P channels
Heteromerization is a cost-effective mean for a cell to acquire new functions by generating
new channels with specific regulations and behaviors. Another way is the modulation of existing
channels by auxiliary proteins that can affect different properties such as channel trafficking or
gating. This is well exemplified on TREK1 and TREK2. Indeed, binding of the A-Kinase
Anchoring Protein (AKAP)-150 to a main regulatory site adjacent to the M4 domain stimulates
TREK1 and TREK2 activity (Sandoz et al. 2006) whereas interaction with microtubule-
associated protein 2 (Mtap2) increases recruitment of the channels at the cell surface in a tubulin-
dependent manner (Sandoz et al. 2008). COP-I also promotes TREK1 distribution at the cell
surface (Kim et al. 2010) and so does its interaction with the neurotensin receptor (NTR)
3/sortilin, a protein located mostly in the trans golgi network and involved in intracellular
trafficking (Mazella et al. 2010). On the contrary the binding of spadin, a peptide derived from
the maturation of NTR3/sortilin, causes TREK1 inhibition and internalization. Also, association
of TREK1 with the prion protein PrPc has been reported, but its relevance has not been
documented yet (Azzalin et al. 2006). Other K2P are controlled by the interaction with partner
proteins. The presence of TASK1 and TASK3 at the plasma membrane is the result of a fine
balance between the mutually exclusive binding of COP-I (retrieval to the ER) and 14-3-3
(forward signal) (O’Kelly et al. 2002; Zuzarte et al. 2009). TASK1 also interacts with p11,
however the role of this interaction is not clear (Girard et al. 2002; Renigunta et al. 2006). Finally,
endosomal SNARE protein syntaxin-8 interacts with TASK1 and promotes its internalization.
TWIK1 interacts with a complex made of the small G protein ARF6 and its nucleotide exchange
factor EFA6 that are elements of the internalization machinery. TWIK1 binding to a complex
comprising EFA6/ARF6GDP would favor the exchange of GDP by GTP, the recruitment of coat

This article is protected by copyright. All rights reserved. 6
proteins and the constitutive endocytosis of the channel (Decressac et al. 2004). In the case of
TRESK, interaction with the calcium/calmodulin-dependent protein phosphatase calcineurin
changes its regulation since it provides the channel with sensitivity to intracellular Ca2+ (Czirják et
al. 2004). TRESK channel also interacts with 14-3-3 (Czirják et al. 2008) and tubulin (Enyedi et al.
2014).
Regulation of K2P channels by G protein-mediated pathways
Signaling pathways related to the activation of G protein-coupled receptors by hormones
and neurotransmitters affect K2P channels in various ways. In some cases, G protein activation
affects cellular trafficking. For instance, activation of Gi-coupled receptors may increase TWIK1
current through relocation of endosomal channels to the cell surface (Feliciangeli et al. 2010).
THIK2 ER retention signal contains a consensus PKA site, suggesting that this signaling
pathway could be involved in its exit of ER and relocation to the plasma membrane (Chatelain et
al. 2013). More often, G protein activation directly affects the gating properties of K2P channels.
For instance, TRESK/calcineurin interaction causes dephosphorylation and activation of
TRESK, hence coupling channel activity to the level of intracellular Ca2+ (Czirják et al. 2004). On
the contrary, stimulation of Gq-coupled receptors leads to an inhibition of TASK channels
(Chen et al. 2006). TREK1 and TREK2 are inhibited by stimulation of Gq-activated protein
kinase C (PKC) and Gs-activated PKA (Fink et al. 1996; Lesage et al. 2000) although some
studies also suggest an effect via the depletion of PIP2 (Lopes et al. 2005). The C-ter of these
channels have phosphorylation sites for each kinase, and the phosphorylation by one kinase
seems to favor the action of the other one (Murbartián et al. 2005; Kang et al. 2006). Another way
for G proteins to modulate K2P activity is by directly interacting with the channels. It has been
established that G can bind directly to the cytoplasmic C-termini of TASK2 and TREK1 with
opposite results, i.e. inhibition of TASK2 (Añazco et al. 2013) and opening of TREK1 (Woo et al.
2012).
Effect of lipids and physical parameters
K2P channels are sensitive to different lipids. For instance, arachidonic acid and other
polyunsaturated fatty acids (PUFAs) inhibit TRESK (Sano et al. 2003) whereas they activate
TREK1 (Patel et al. 1998), TREK2 (Bang et al. 2000; Lesage et al. 2000) and TRAAK (Fink et al.
1998). Through the production of phosphatidic acid, phospholipase D2 (PLD2) potentiates the
activity of TREK1 and TREK2, but not TRAAK, (Comoglio et al. 2014). TREK/TRAAK
channels are the only K2P activated by a mechanical stretch of the membrane. The membrane-
spanning helices (primarily M4) and the C-ter region close to M4 play a pivotal role in this
regulation (Patel et al. 1998; Honoré et al. 2002). This mechanical sensitivity does not depend on a
tether-mediated mechanism but comes directly from the lipid bilayer (Brohawn et al. 2014).
TREK/TRAAK channels are very sensitive to temperature. A 10 °C rise enhances TREK1
current amplitude by approximately 7-fold. In cells transfected with TREK2 or TRAAK, a rise
from 24°C to 42°C causes the whole-cell currents to increase about 20-fold (Maingret et al.
2000a; Kang et al. 2005).
Physiology and pathophysiology of K2P channels
The role of the K2P channels in the control of the membrane potential, and therefore of
cellular excitability, mark them as potential players in a number of biological functions. The K2P
channels display very diverse expression patterns, from almost ubiquitous as TWIK1 to
restricted to a subset of cells, as TALK1 that is almost exclusively expressed in the exocrine
pancreas. The field is active to develop drugs targeting K2P channels (Bagriantsev et al. 2013;
Rodrigues et al. 2014) and some specific inhibitors have been recently described, such as spadin
that inhibits TREK1 with an affinity in the nanomolar range (Mazella et al. 2010). Nonetheless,
tools are still very limited, and this lack has hindered the investigations of the physiological roles

This article is protected by copyright. All rights reserved. 7
of the K2P channels by classical pharmacological approaches. As a consequence, most of the
information came from the study of transgenic animal models, essentially from mice with
inactivated KCNK genes (Sabbadini & Yost, 2009). These mice do not show anatomic
abnormalities and breed normally. The only exception is TASK2 for which two studies have
reported a reduced viability due to increased mortality in the neonatal period (Gerstin et al. 2003;
Warth et al. 2004). Subtle alterations in different physiological processes have been reported,
some correlated and others causative of a disease (Table 2). Here, we will only present a few
relevant examples of the studies that link K2P channels to physiopathology. More detailed
description can be found elsewhere, such as in (Bayliss & Barrett, 2008; Sabbadini & Yost, 2009;
Enyedi & Czirják, 2010; Es-Salah-Lamoureux et al. 2010; Lesage & Barhanin, 2011).
Some phenotypes are directly linked to the regulations or the pharmacological properties
of the inactivated channel. For example, knocking out volatile anesthetic-activated K2P channels
TASK1/3 and TREK1 produces an anesthetic-resistant phenotype (Heurteaux et al. 2004;
Linden et al. 2006, 2007). TREK1 sensitivity to PUFAs forms a basis for the neuroprotective
effects afforded by PUFAs against cerebral ischemia (Heurteaux et al. 2004) since opening of the
channel by PUFAs would lower cell excitability and excitotoxicity. Similarly, the higher
thresholds for thermal and mechanical nociception, as well as hyperalgesia in inflammation
conditions, observed in TREK1 KO mice seem to be associated with the sensitivity of TREK1
to temperature and mechanical stimulation (Alloui et al. 2006; Noël et al. 2009). Indeed, in
nociceptor neurons of dorsal root ganglia (DRG) both types of stimuli activate TREK1, causing
hyperpolarization and attenuation of the signal. TREK2 and TRAAK are also involved in
mechanical and thermal sensation, with specificities that make the three channels complementary
(Pereira et al. 2014). TRESK is also abundant in DRG and other sensory ganglia, and hence
could potentially play a role in nociception. Blocking or silencing the channel was reported to
modify nociceptor excitability (Tulleuda et al. 2011) but no phenotype could be observed in the
TRESK KO mice (Dobler et al. 2007). TASK1 and TASK3 are sensitive to pH and expressed in
several nuclei or bodies with chemosensory functions. Therefore a role as sensors of PCO2 by
sensing acidosis was suspected early on. Using a pharmacological approach as well as single-
channel current analysis, it was shown that TASK1, TASK3 and mostly TASK1/TASK3
heterodimers play an important role in chemoreception in the carotid bodies, the primary
sensors of hypoxia and metabolic acidosis (Buckler et al. 2000; Kim et al. 2009). Data also support
a role of TASK channels in the sensitivity of neuroepithelial bodies to PO2 (Hartness et al. 2001).
TASK1 and TASK3 are expressed in several nuclei of the brain stem that monitor PCO2, but
studies, notably on KO models, argue against a role of these channels in the central respiratory
chemosensitivity (Mulkey et al. 2007). The role of TALK channels was sudied in conditions
linked to alkalinization. Data from KO mice suggest that TASK2 is engaged in bicarbonate
reabsorption in the kidney and the accompanying Na+ and water movements (Warth et al. 2004).
Activation of the channel by HCO3
--mediated alkalization generates a K+ flux that
counterbalances the depolarization caused by the Na+-3-HCO3
- cotransporter and hence enables
the upholding of HCO3
- flux (L’Hoste et al. 2007). A similar role has been suggested for TASK2,
TALK1 and TALK2 in epithelial cells of the exocrine pancreas, based on their abundant
expression in these cells (Fong et al. 2003). Also, TASK2 activation is necessary for volume
regulation of native renal proximal tubule cells (Barriere et al. 2003). Finally, TASK2 is expressed
in retrotrapezoid nucleus neurons, a population of which is involved in CO2 and O2 sensing, and
TASK2 KO mice exhibit alteration in their breathing behavior following hypoxia or exposure to
low CO2 (Gestreau et al. 2010). These data suggest a major role of TASK2 channel in the central
O2 chemosensitivity.
Even without stimulation, basal background conductance produced by K2P channels play a
role in cellular excitability and development of different tissue. In the brain TREK1 participates
in serotoninergic transmission, which is increased in the TREK1 KO mice (Heurteaux et al. 2006).
This affects animal behavior, KO mice displaying a depression-resistant phenotype in a large

This article is protected by copyright. All rights reserved. 8
battery of assays for the evaluation of helplessness and despair. A similar phenotype was
observed on mice treated with the TREK1 inhibitor spadin (Moha Ou Maati et al. 2012). These
results mark TREK1 as a potential target for antidepressant development (Borsotto et al. 2014).
Other effects of TREK1 inactivation have been observed, supporting other roles. For instance,
recent data suggest that TREK1 is required for the integrity of the blood-brain barrier (Bittner et
al. 2013, 2014). In TREK1 KO mice, leukocytes transmigration is increased in autoimmune
encephalomyelitis, an experimental model of blood-brain barrier dysfunction related to
inflammation. TREK1 inactivation is associated with aggravated symptoms and increased cellular
infiltrates in the CNS, whereas TREK1 activation by riluzole or -linolenic acid attenuates the
severity of the symptoms in wild-type animals. TASK channels are another example of leak K+
channels involved in both cellular excitability and development. In cerebellar granule cells, the
spillover of synaptically released GABA gives rise to a persistent inhibitory conductance
mediated by the GABAA receptor. However when this receptor is inactivated no change is
observed on the membrane potential because of a spontaneous compensation by overexpression
of TASK1 and TASK3 (Brickley et al. 2001; Aller et al. 2005). In the cerebellum, TASK3
expression correlates with massive neuronal apoptosis during development (Lauritzen et al. 2003).
On the other hand, TASK3 overexpression increases cell survival and causes cell proliferation of
transformed fibroblasts (Mu et al. 2003). Together these results suggest that TASK3 plays a dual
role in proliferation or apoptosis depending on the context. Surprisingly, TASK3 KO mice
display only minor impairment in locomotion. However, they present alterations such as
impaired working memory and perturbation in the regulation of the circadian rhythm (Linden et
al. 2007), which, together with the resistance of these mice to antidepressants, suggest an
involvement of TASK3 in the mechanisms of depression (Gotter et al. 2011). In the
hypothalamic orexin neurons, a role in glucose sensing was proposed for TASK channels
(Burdakov et al. 2006), however the function is preserved in TASK1/TASK3 double KO mice
(Guyon et al. 2009; González et al. 2009). In rat adrenal glomerulosa cells, TASK channels are
responsible for the high resting conductance, with a major contribution of TASK3 (Czirják et al.
2000; Czirják & Enyedi, 2002b; Lotshaw, 2006). Knockout of TASK1 or both TASK1 and
TASK3 causes primary hyperaldosteronism (Heitzmann et al. 2008; Davies et al. 2008). In
TASK1 KO mice, aldosterone overproduction is a consequence of an inappropriate zonation of
the adrenal gland (Heitzmann et al. 2008). Only immature mice and females are affected. This
points out an unexpected role of TASK1 in the development and zonation of adrenal cortex. It
also shows that for this function, TASK3 cannot compensate for the absence of TASK1. The
predominant role of TASK1 is also attested in human adrenal glands (Nogueira et al. 2010). In
bovine tissue, the role in aldosterone secretion appears to be played by TREK1 (Enyeart et al.
2004). In the heart, TASK1 is predominantly expressed in the ventricle in rodents, and KO mice
show a ventricular phenotype with prolonged QT interval, wide QRS, and increased ventricular
action potential duration (Decher et al. 2011; Donner et al. 2011). In human, however, TASK1 is
mostly found in the atria, leading to the proposal that it could be involved in atrial fibrillation
(AF). This possibility is strengthened by the fact that mutations found in patients with AF alter
atrial TASK1 current in zebrafish (Liang et al. 2014). TWIK2 is highly expressed in the vascular
system and inactivation of its gene is associated with vascular and pulmonary hypertension
(Lloyd et al. 2011; Pandit et al. 2014). In astrocytes (Wang et al. 2013), renal cells (Millar et al.
2006) and pancreas ß cells (Chatelain et al. 2012), TWIK1 gene inactivation causes an
hyperpolarization of the resting membrane potential, which is explained by the dynamic ion
selectivity of the channel.

This article is protected by copyright. All rights reserved. 9
K2P channels in human pathologies
Dynamic ion selectivity of TWIK1 can account for the paradoxical depolarization of
human cardiomyocytes observed in subphysiological K+, a phenomenon that may stem cardiac
arrhythmias (Chen et al. 2014). A dominant-negative mutation in the gene encoding TRESK
segregates with a phenotype of migraine with aura (Lafrenière et al. 2010). However, another
loss-of-function mutation of TRESK could not be associated with the phenotype (Maher et al.
2013) suggesting a multigenic origin of this hereditary disease. The relationship to a genetic
disorder is more straightforward for other K2P channels. In human, whole-exome sequencing of
multiple patients with pulmonary arterial hypertension has revealed a correlation between the
pathology and several missense mutations that all abolish TASK1 activity (Ma et al. 2013). This
fits well with the reports that TASK1 is sensitive to hypoxia and plays a role in the regulation of
the pulmonary vascular tone (Gurney et al. 2003). Genome studies revealed that TASK3 is
genetically imprinted, i.e. it is only expressed from the maternal allele, and that a missense
mutation (G236R) is associated with the Birk-Barel syndrom, a maternally transmitted syndrome
of mental retardation, hypotonia and unique dysmorphism with elongated face (Barel et al. 2008).
The original study reported that the mutation produces a dominant-negative TASK3 subunit,
resulting in non functional TASK3 homodimers and TASK1/TASK3 hetetrodimers (Barel et al.
2008). However, others have described that the mutated subunit still produces current, although
significantly decreased with altered properties (Veale et al. 2014). In a patient with a severe
cardiac phenotype of cardiac arrhythmia, in addition to a mutation in the cardiac sodium channel
SCN5A, another mutation was identified in the M1P1 loop of TALK2 (G88R) that causes a gain
of function and an increase of the channel conductance (Friedrich et al. 2014). This increased
activity is likely to promote repolarization of the cardiac action potential and to shorten refectory
period, which therefore might favor reentry arrhythmias. This example illustrates the need for a
tight control of K2P channels activity within physiological margins. TASK3 is another example.
In cell and animal models, TASK3 has been demonstrated to be involved in both cell apoptosis
and survival. As mentioned above, the channel is both associated with massive apoptosis in
developing cerebellum, and with survival and proliferation when overexpressed in fibroblasts
(Mu et al. 2003; Lauritzen et al. 2003). This suggests that this channel could play different roles
depending on its regulations and therefore that TASK3 could shift from a function to the other
upon a change in its environment with potential physiopathological consequences. Along this
line, overexpression of the channel has been reported in many different types of human cancers
(Mu et al. 2003). Actually, all but three K2P channels (TRAAK, TALK1 and TRESK) have their
expression modified in different oncogenic processes (Williams et al. 2013). For instance, TWIK1
is among the top 1% of genes with altered expression in different types of human cancers, either
increased (bladder, lung, pancreas) or decreased (cancers of the central nervous system). Its
expression varies in ovarian and prostate cancers, decreasing with tumor progression. Similarly,
TREK exhibits modified expression in a variety of cancer types such as lung or brain cancers.
Although it was demonstrated in some cases that the activity of the channel is required to
observe the oncogenic effect (Pei et al. 2003), more work is necessary to conclude whether
altered expression is a cause or a consequence of the carcinogenesis.
Conclusions
Since the serendipitous identification of TWIK1 in 1996, we have learned a lot about the
diversity and nature of K2P channels. Far from forming mere K+ leaks in the plasma membrane,
they have proven to be exquisitely regulated by a wide variety of mechanisms. K2P channels
affect cell excitability and biology, and are involved in the normal development and functioning
of many tissues including brain, heart, adrenals glands and kidneys. This field of research
continues to evolve rapidly, constantly improving our understanding of their physiological and
pathological roles. New fascinating questions emerge from recent data. The studies on “silent”
channels suggest that some of these K2P channels may have a role in intracellular compartments

This article is protected by copyright. All rights reserved. 10
(TWIK1 in recycling endosomes and THIK2 and KCNK7 in the ER) and the presence of a
hydrophobic barrier in the deep pore of some of them supports the existence of a new type of
gate. How and by which stimuli this hydrophobic gate is controlled remain open questions. By
suggesting that K+ channels may fulfill inhibitory and excitatory roles traditionally attributed to
distinct classes of ion channels, the recent demonstration that TWIK1 exhibits dynamic ion
selectivity opens new areas of research. Which K2P channels exhibit this behavior, which stimuli
can influence their ionic selectivity, what are the impacts on cell biology constitute fascinating
interrogations. Finally, the therapeutic interest of these K2P channels stands very high. Drugs
targeting K2P channels may be relevant for treating disorders as diverse as depression, pain,
vascular and pulmonary hypertension and cancer.
Acknowledgements
Authors are supported by the Fondation pour la Recherche Médicale (Equipe labellisée FRM
2011) and by the French Government (National Research Agency, ANR) through the
“Investments for the Future” Program, grant ANR-11-LABX-0015-01.
Legends of the tables and figure
Table 1
Natural and chemical effectors of K2P channels, remarkable features and interacting partners.
Table 2
Pathophysiology of K2P channels deduced from cell and animal models, and implications in
human pathologies.

This article is protected by copyright. All rights reserved. 11
Figure 1
Structural organization of K2P channels
A, Schematic representation of K2P subunit organization with the two pore-domains (in pink),
the four transmembrane domains (in blue), and the extracellular cap (in green).
B, 3D reconstruction of TWIK1 deduced from the crystal structure (Miller & Long, 2012) (PDB
ID code 3UKM). The different domains are represented with the same color code as in A,
C, Dendrogram of the fifteen K2P subunits with their conventional and systematic name.

This article is protected by copyright. All rights reserved. 12
Table 1
Name
Activators
Inhibitors
Remarkable features
Interacting partners
TWIK1
K2P1.11
Gi-coupled receptor-mediated
trafficking to the cell surface2
acid pHi1
PKC1
endosomal distribution2/
SUMO silencing3
dynamic ion selectivity4
heteromerization with other
K2P5,6
weak inward rectification1
EFA6/ARF6GDP7
SUMO ?3
TWIK2
K2P6.18–10
slow inactivation10
KCNK7
K2P7.111
no current11
TREK1
K2P2.112
NO13
copper14
Gß15
ML67-3316
substituted
caffeate
esters17
acid pHi18,19
volatile
anesthetics
(halothane,
isoflurane,
chloroform)
19,20
mechanical
stretch
19,21,22
PUFA
19,23,24
LP25
temperature
26,27
riluzole
19,28
zinc14
acid pHo29
fluoxetine30
spadin31
Gs, Gq
(PKA, PKC)
12,19
multiple unitary conductances
32,33
alternative transcription initiation
34,35
COP-I36
PrPc37
AKAP15038
mtap239
PLD240
TREK2
K2P10.1
19,24
acid pHo41
Gi19
alkaline
pHo41
fluoxetine42
TRAAK1
K2P4.123
alkaline pHi43
acid pH41
ruthenium
red44
TASK1
K2P3.145
alkaline pHo45
volatile
anesthetics
(halothane,
isoflurane)
20,46
hypoxia47
acid pHo
45,48,49
Gq50
sanshool51
heteromerization
TASK1/TASK344,52
no cys bond in the cap45,48,49
dynamic ion selectivity53
relatively slow time-dependent
activation54,55
p1156
syntaxin-857
14.3-358,59
COP-I58,59
TASK3
K2P9.1
48,49
copper14
zinc14
ruthenium
red44
TASK5
K2P15.1
60,61
no current60,61
TASK2
K2P5.162
alkaline pHi63
alkaline pHo62,64
Gß65
relatively slow time-dependent
activation62
TALK1
K2P16.166
NO and reactive
oxygen species67
TALK2
K2P17.166

This article is protected by copyright. All rights reserved. 13
THIK1
K2P13.168
arachidonic acid68
hypoxia69
halothane
68,70
no pH
sensitivity
68
heteromerization
THIK1/THIK2
71
THIK2
K2P12.1
66,68
ER
retention
70,72
TRESK
K2P18.173
volatile anesthetics74
calcium75
Gq75
PKC76
PUFA73
sanshool51
asymmetrical gating behavior75
no pH sensitivity in the
physiological range73
14.3-377
calcineurin75
tubulin78
1-Lesage et al. 1996; 2-Feliciangeli et al. 2010; 3-Rajan et al. 2005; 4-Chatelain et al. 2012; 5-Hwang et al. 2014; 6-Plant et al. 2012; 7-
Decressac et al. 2004; 8-Chavez et al. 1999; 9-Pountney et al. 1999; 10-Patel et al. 2000; 11-Salinas et al. 1999; 12-Fink et al. 1996;
13-Koh et al. 2001; 14-Gruss et al. 2004; 15-Woo et al. 2012; 16-Bagriantsev et al. 2013; 17-Rodrigues et al. 2014; 18-Maingret et al.
1999; 19-Lesage et al. 2000; 20-Patel et al. 1999; 21-Maingret et al. 1999; 22-Patel et al. 1998; 23-Fink et al. 1998; 24-Bang et al. 2000;
25-Maingret et al. 2000b; 26-Maingret et al. 2000a; 27-Kang et al. 2005; 28-Duprat et al. 2000; 29-Cohen et al. 2008; 30-Kennard et
al. 2005; 31-Mazella et al. 2010; 32-Li et al. 2006; 33-Kang et al. 2007; 34-Thomas et al. 2008; 35-Simkin et al. 2008; 36-Kim et al.
2010; 37-Azzalin et al. 2006; 38-Sandoz et al. 2006; 39-Sandoz et al. 2008; 40-Comoglio et al. 2014; 41-Sandoz et al. 2009; 42-Kang
et al. 2012; 43-Kim et al. 2001a; 44-Czirják & Enyedi 2002; 45-Duprat et al. 1997; 46-Talley & Bayliss 2002; 47-Kemp et al. 2004;
48-Kim et al. 2000; 49-Rajan et al. 2000; 50-Chen et al. 2006; 51-Bautista et al. 2008; 52-Lauritzen et al. 2003; 53-Ma et al. 2012; 54-
Lopes et al. 2000; 55-Meadows & Randall 2001; 56-Girard et al. 2002; 57-Renigunta et al. 2014; 58-O’Kelly et al. 2002; 59-Zuzarte
et al. 2009; 60-Kim & Gnatenco 2001; 61-Ashmole et al. 2001; 62-Reyes et al. 1998; 63-Niemeyer et al. 2010; 64-Kang & Kim
2004; 65-Añazco et al. 2013; 66-Girard et al. 2001; 67-Duprat et al. 2005; 68-Rajan et al. 2001; 69-Campanucci et al. 2005; 70-
Chatelain et al. 2013; 71-Blin et al. 2014; 72-Renigunta et al. 2014; 73-Sano et al. 2003; 74-Liu et al. 2004; 75-Czirják et al. 2004; 76-
Rahm et al. 2012; 77-Czirják et al. 2008; 78-Enyedi et al. 2014.

This article is protected by copyright. All rights reserved. 14
Table 2
Name
Physiology/Pathophysiology
Human pathologies
TWIK1
K2P1.11
phosphate and water reabsorption in kidney2
cancer ?3
paradoxical depolarization of
cardiomyocytes in
hypokaliemia/arrythmia4
TWIK2
K2P6.15–7
vascular8 and pulmonary9 hypertension
KCNK7
K2P7.110
no altered phenotype11
TREK1
K2P2.112
cytoskeletal organization during neuronal
morphogenesis13
depression14
neuroprotection15
integrity of blood-brain barrier16
vasodilatation17,18
modulation of thermal and
mechanical nociception, and
hyperalgesia in inflammation
conditions19–21
cancer ? 22
TREK2
K2P10.123,24
TRAAK1
K2P4.125
brain metabolism26
TASK1
K2P3.127
adrenal gland zonation28
modulation of auto-immune inflammation29
aldosterone secretion30–32
proliferation/apoptosis33
pulmonary arterial
hypertension34
atrial fibrillation35
cancer ?36,37
TASK3
K2P9.138,39
sleep mechanisms and cognitive functions40
neuronal migration during development41
depression42
Birk-Barel
syndrome43
TASK5
K2P15.144,45
TASK2
K2P5.146
bicarbonate reabsorption47
volume control in kidney proximal tubule48
volume regulation of T-cells49
central chemoreception50
cancer ?51
TALK1
K2P16.152
TALK2
K2P17.152
cardiac conduction disorder53
THIK1
K2P13.154
THIK2
K2P12.152,54
TRESK
K2P18.155
temperature nociception56
migraine57,58
1-Lesage et al. 1996; 2-Nie et al. 2005; 3-Beitzinger et al. 2008; 4-Ma et al. 2011; 5-Chavez et al. 1999; 6-Pountney et al. 1999; 7-Patel
et al. 2000; 8-Lloyd et al. 2011; 9-Pandit et al. 2014; 10-Salinas et al. 1999; 11-Yost et al. 2008; 12-Fink et al. 1996; 13-Lauritzen et al.
2005; 14-Heurteaux et al. 2006; 15-Heurteaux et al. 2004; 16-Bittner et al. 2013; 17-Blondeau et al. 2007; 18-Garry et al. 2007; 19-
Alloui et al. 2006; 20-Pereira et al. 2014); 21-Noël et al. 2009; 22-Voloshyna et al. 2008; 23-Lesage et al. 2000; 24-Bang et al. 2000;
25-Fink et al. 1998; 26-Laigle et al. 2012; 27-Duprat et al. 1997; 28-Heitzmann et al. 2008; 29-Bittner et al. 2009; 30-Davies et al.
2008; 31-Guagliardo et al. 2012; 32-Penton et al. 2012; 33-Lauritzen et al. 2003; 34-Ma et al. 2013; 35-Liang et al. 2014; 36-Mu et al.
2003; 37-Pei et al. 2003; 38-Kim et al. 2000; 39-Rajan et al. 2000; 40-Linden et al. 2007; 41-Bando et al. 2014; 42-Gotter et al. 2011;
43-Barel et al. 2008; 44-Kim & Gnatenco 2001; 45-Ashmole et al. 2001; 46-Reyes et al. 1998; 47-Warth et al. 2004; 48-Barriere et al.
2003; 49-Bobak et al. 2011; 50-Gestreau et al. 2010; 51-Alvarez-Baron et al. 2011; 52-Girard et al. 2001; 53-Friedrich et al. 2014; 54-
Rajan et al. 2001; 55-Sano et al. 2003; 56-Chae et al. 2010; 57-Lafrenière et al. 2010; 58-Maher et al. 2013.

This article is protected by copyright. All rights reserved. 15
References
Aller MI, Veale EL, Linden A-M, Sandu C, Schwaninger M, Evans LJ, Korpi ER, Mathie A,
Wisden W & Brickley SG (2005). Modifying the Subunit Composition of TASK Channels Alters
the Modulation of a Leak Conductance in Cerebellar Granule Neurons. J Neurosci 25, 11455–
11467.
Alloui A, Zimmermann K, Mamet J, Duprat F, Noël J, Chemin J, Guy N, Blondeau N, Voilley
N, Rubat-Coudert C, Borsotto M, Romey G, Heurteaux C, Reeh P, Eschalier A & Lazdunski M
(2006). TREK-1, a K+ channel involved in polymodal pain perception. EMBO J 25, 2368–2376.
Alvarez-Baron CP, Jonsson P, Thomas C, Dryer SE & Williams C (2011). The two-pore domain
potassium channel KCNK5: induction by estrogen receptor alpha and role in proliferation of
breast cancer cells. Mol Endocrinol Baltim Md 25, 1326–1336.
Añazco C, Peña-Münzenmayer G, Araya C, Cid LP, Sepúlveda FV & Niemeyer MI (2013). G
protein modulation of K2P potassium channel TASK-2 : a role of basic residues in the C
terminus domain. Pflüg Arch Eur J Physiol 465, 1715–1726.
Aryal P, Abd-Wahab F, Bucci G, Sansom MSP & Tucker SJ (2014). A hydrophobic barrier deep
within the inner pore of the TWIK-1 K2P potassium channel. Nat Commun 5, 4377.
Ashmole I, Goodwin PA & Stanfield PR (2001). TASK-5, a novel member of the tandem pore
K+ channel family. Pflüg Arch Eur J Physiol 442, 828–833.
Azzalin A, Ferrara V, Arias A, Cerri S, Avella D, Pisu MB, Nano R, Bernocchi G, Ferretti L &
Comincini S (2006). Interaction between the cellular prion (PrPC) and the 2P domain K+
channel TREK-1 protein. Biochem Biophys Res Commun 346, 108–115.
Bagriantsev SN, Ang K-H, Gallardo-Godoy A, Clark KA, Arkin MR, Renslo AR & Minor DL
(2013). A high-throughput functional screen identifies small molecule regulators of temperature-
and mechano-sensitive K2P channels. ACS Chem Biol 8, 1841–1851.
Bagriantsev SN, Clark KA & Minor DL (2012). Metabolic and thermal stimuli control K(2P)2.1
(TREK-1) through modular sensory and gating domains. EMBO J 31, 3297–3308.
Bagriantsev SN, Peyronnet R, Clark KA, Honoré E & Minor DL (2011). Multiple modalities
converge on a common gate to control K2P channel function. EMBO J 30, 3594–3606.
Bando Y, Hirano T & Tagawa Y (2014). Dysfunction of KCNK potassium channels impairs
neuronal migration in the developing mouse cerebral cortex. Cereb Cortex N Y N 1991 24, 1017–
1029.
Bang H, Kim Y & Kim D (2000). TREK-2, a new member of the mechanosensitive tandem-
pore K+ channel family. J Biol Chem 275, 17412–17419.
Barel O, Shalev SA, Ofir R, Cohen A, Zlotogora J, Shorer Z, Mazor G, Finer G, Khateeb S,
Zilberberg N & Birk OS (2008). Maternally inherited Birk Barel mental retardation dysmorphism
syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J
Hum Genet 83, 193–199.
Barriere H, Belfodil R, Rubera I, Tauc M, Lesage F, Poujeol C, Guy N, Barhanin J & Poujeol P
(2003). Role of TASK2 potassium channels regarding volume regulation in primary cultures of
mouse proximal tubules. J Gen Physiol 122, 177–190.
Bautista DM, Sigal YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA & Julius D
(2008). Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore
potassium channels. Nat Neurosci 11, 772–779.
Bayliss DA & Barrett PQ (2008). Emerging roles for two-pore-domain potassium channels and
their potential therapeutic impact. Trends Pharmacol Sci 29, 566–575.
Beitzinger M, Hofmann L, Oswald C, Beinoraviciute-Kellner R, Sauer M, Griesmann H, Bretz
AC, Burek C, Rosenwald A & Stiewe T (2008). p73 poses a barrier to malignant transformation

This article is protected by copyright. All rights reserved. 16
by limiting anchorage-independent growth. EMBO J 27, 792–803.
Berg AP, Talley EM, Manger JP & Bayliss DA (2004). Motoneurons express heteromeric TWIK-
related acid-sensitive K+ (TASK) channels containing TASK-1 (KCNK3) and TASK-3
(KCNK9) subunits. J Neurosci Off J Soc Neurosci 24, 6693–6702.
Bichet D, Blin S, Feliciangeli S, Chatelain FC, Bobak N & Lesage F (2014). Silent but not dumb:
how cellular trafficking and pore gating modulate expression of TWIK1 and THIK2. Pflugers
Arch; DOI: 10.1007/s00424-014-1631-y.
Bittner S, Meuth SG, Göbel K, Melzer N, Herrmann AM, Simon OJ, Weishaupt A, Budde T,
Bayliss DA, Bendszus M & Wiendl H (2009). TASK1 modulates inflammation and
neurodegeneration in autoimmune inflammation of the central nervous system. Brain J Neurol 132,
2501–2516.
Bittner S, Ruck T, Fernández-Orth J & Meuth SG (2014). TREK-king the blood-brain-barrier. J
Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol 9, 293–301.
Bittner S, Ruck T, Schuhmann MK, Herrmann AM, Moha ou Maati H, Bobak N, Göbel K,
Langhauser F, Stegner D, Ehling P, Borsotto M, Pape H-C, Nieswandt B, Kleinschnitz C,
Heurteaux C, Galla H-J, Budde T, Wiendl H & Meuth SG (2013). Endothelial TWIK-related
potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS. Nat Med 19,
1161–1165.
Blin S, Chatelain FC, Feliciangeli S, Kang D, Lesage F & Bichet D (2014). Tandem Pore Domain
Halothane-Inhibited K+ Channel Subunits THIK1 and THIK2 Assemble and Form Active
Channels. J Biol Chem; DOI: 10.1074/jbc.M114.600437.
Blondeau N, Pétrault O, Manta S, Giordanengo V, Gounon P, Bordet R, Lazdunski M &
Heurteaux C (2007). Polyunsaturated fatty acids are cerebral vasodilators via the TREK-1
potassium channel. Circ Res 101, 176–184.
Bobak N, Bittner S, Andronic J, Hartmann S, Mühlpfordt F, Schneider-Hohendorf T, Wolf K,
Schmelter C, Göbel K, Meuth P, Zimmermann H, Döring F, Wischmeyer E, Budde T, Wiendl
H, Meuth SG & Sukhorukov VL (2011). Volume regulation of murine T lymphocytes relies on
voltage-dependent and two-pore domain potassium channels. Biochim Biophys Acta 1808, 2036–
2044.
Bockenhauer D, Zilberberg N & Goldstein S a. N (2001). KCNK2: reversible conversion of a
hippocampal potassium leak into a voltage-dependent channel. Nat Neurosci 4, 486–491.
Borsotto M, Veyssiere J, Moha Ou Maati H, Devader C, Mazella J & Heurteaux C (2014).
Targeting two pore domain K(+) channels TREK-1 and TASK-3 for the treatment of
depression: A new therapeutical concept. Br J Pharmacol; DOI: 10.1111/bph.12953.
Brickley SG, Revilla V, Cull-Candy SG, Wisden W & Farrant M (2001). Adaptive regulation of
neuronal excitability by a voltage- independent potassium conductance. Nature 409, 88–92.
Brohawn SG, del Mármol J & MacKinnon R (2012). Crystal structure of the human K2P
TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335, 436–441.
Brohawn SG, Su Z & MacKinnon R (2014). Mechanosensitivity is mediated directly by the lipid
membrane in TRAAK and TREK1 K+ channels. Proc Natl Acad Sci U S A 111, 3614–3619.
Buckler KJ, Williams BA & Honore E (2000). An oxygen-, acid- and anaesthetic-sensitive
TASK-like background potassium channel in rat arterial chemoreceptor cells. J Physiol 525 Pt 1,
135–142.
Burdakov D, Jensen LT, Alexopoulos H, Williams RH, Fearon IM, O’Kelly I, Gerasimenko O,
Fugger L & Verkhratsky A (2006). Tandem-pore K+ channels mediate inhibition of orexin
neurons by glucose. Neuron 50, 711–722.
Campanucci VA, Brown ST, Hudasek K, O’kelly IM, Nurse CA & Fearon IM (2005). O2
sensing by recombinant TWIK-related halothane-inhibitable K+ channel-1 background K+

This article is protected by copyright. All rights reserved. 17
channels heterologously expressed in human embryonic kidney cells. Neuroscience 135, 1087–1094.
Chae YJ, Zhang J, Au P, Sabbadini M, Xie G-X & Yost CS (2010). Discrete change in volatile
anesthetic sensitivity in mice with inactivated tandem pore potassium ion channel TRESK.
Anesthesiology 113, 1326–1337.
Chatelain FC, Bichet D, Douguet D, Feliciangeli S, Bendahhou S, Reichold M, Warth R,
Barhanin J & Lesage F (2012). TWIK1, a unique background channel with variable ion selectivity.
Proc Natl Acad Sci U S A 109, 5499–5504.
Chatelain FC, Bichet D, Feliciangeli S, Larroque M-M, Braud VM, Douguet D & Lesage F
(2013). Silencing of the tandem pore domain halothane-inhibited K+ channel 2 (THIK2) relies
on combined intracellular retention and low intrinsic activity at the plasma membrane. J Biol
Chem 288, 35081–35092.
Chavez RA, Gray AT, Zhao BB, Kindler CH, Mazurek MJ, Mehta Y, Forsayeth JR & Yost CS
(1999). TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium
channel family. J Biol Chem 274, 7887–7892.
Chen H, Chatelain FC & Lesage F (2014). Altered and dynamic ion selectivity of K(+) channels
in cell development and excitability. Trends Pharmacol Sci; DOI: 10.1016/j.tips.2014.06.002.
Chen X, Talley EM, Patel N, Gomis A, McIntire WE, Dong B, Viana F, Garrison JC & Bayliss
DA (2006). Inhibition of a background potassium channel by Gq protein alpha-subunits. Proc
Natl Acad Sci U S A 103, 3422–3427.
Cohen A, Ben-Abu Y, Hen S & Zilberberg N (2008). A Novel Mechanism for Human K2P2.1
Channel Gating FACILITATION OF C-TYPE GATING BY PROTONATION OF
EXTRACELLULAR HISTIDINE RESIDUES. J Biol Chem 283, 19448–19455.
Comoglio Y, Levitz J, Kienzler MA, Lesage F, Isacoff EY & Sandoz G (2014). Phospholipase
D2 specifically regulates TREK potassium channels via direct interaction and local production of
phosphatidic acid. Proc Natl Acad Sci U S A 111, 13547–13552.
Czirják G & Enyedi P (2002a). Formation of functional heterodimers between the TASK-1 and
TASK-3 two-pore domain potassium channel subunits. J Biol Chem 277, 5426–5432.
Czirják G & Enyedi P (2002b). TASK-3 dominates the background potassium conductance in rat
adrenal glomerulosa cells. Mol Endocrinol Baltim Md 16, 621–629.
Czirják G, Fischer T, Spät A, Lesage F & Enyedi P (2000). TASK (TWIK-related acid-sensitive
K+ channel) is expressed in glomerulosa cells of rat adrenal cortex and inhibited by angiotensin
II. Mol Endocrinol Baltim Md 14, 863–874.
Czirják G, Tóth ZE & Enyedi P (2004). The two-pore domain K+ channel, TRESK, is activated
by the cytoplasmic calcium signal through calcineurin. J Biol Chem 279, 18550–18558.
Czirják G, Vuity D & Enyedi P (2008). Phosphorylation-dependent binding of 14-3-3 proteins
controls TRESK regulation. J Biol Chem 283, 15672–15680.
Davies LA, Hu C, Guagliardo NA, Sen N, Chen X, Talley EM, Carey RM, Bayliss DA & Barrett
PQ (2008). TASK channel deletion in mice causes primary hyperaldosteronism. Proc Natl Acad
Sci U S A 105, 2203–2208.
Decher N, Wemhöner K, Rinné S, Netter MF, Zuzarte M, Aller MI, Kaufmann SG, Li XT,
Meuth SG, Daut J, Sachse FB & Maier SKG (2011). Knock-out of the potassium channel
TASK-1 leads to a prolonged QT interval and a disturbed QRS complex. Cell Physiol Biochem Int J
Exp Cell Physiol Biochem Pharmacol 28, 77–86.
Decressac S, Franco M, Bendahhou S, Warth R, Knauer S, Barhanin J, Lazdunski M & Lesage F
(2004). ARF6-dependent interaction of the TWIK1 K+ channel with EFA6, a GDP/GTP
exchange factor for ARF6. EMBO Rep 5, 1171–1175.
Dobler T, Springauf A, Tovornik S, Weber M, Schmitt A, Sedlmeier R, Wischmeyer E & Döring

This article is protected by copyright. All rights reserved. 18
F (2007). TRESK two-pore-domain K+ channels constitute a significant component of
background potassium currents in murine dorsal root ganglion neurones. J Physiol 585, 867–879.
Donner BC, Schullenberg M, Geduldig N, Hüning A, Mersmann J, Zacharowski K, Kovacevic A,
Decking U, Aller MI & Schmidt KG (2011). Functional role of TASK-1 in the heart: studies in
TASK-1-deficient mice show prolonged cardiac repolarization and reduced heart rate variability.
Basic Res Cardiol 106, 75–87.
Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT &
MacKinnon R (1998). The structure of the potassium channel: molecular basis of K+
conduction and selectivity. Science 280, 69–77.
Duprat F, Girard C, Jarretou G & Lazdunski M (2005). Pancreatic two P domain K+ channels
TALK-1 and TALK-2 are activated by nitric oxide and reactive oxygen species. J Physiol 562,
235–244.
Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C & Lazdunski M (1997). TASK, a human
background K+ channel to sense external pH variations near physiological pH. EMBO J 16,
5464–5471.
Duprat F, Lesage F, Patel AJ, Fink M, Romey G & Lazdunski M (2000). The neuroprotective
agent riluzole activates the two P domain K(+) channels TREK-1 and TRAAK. Mol Pharmacol 57,
906–912.
Enyeart JA, Danthi SJ & Enyeart JJ (2004). TREK-1 K+ channels couple angiotensin II
receptors to membrane depolarization and aldosterone secretion in bovine adrenal glomerulosa
cells. Am J Physiol Endocrinol Metab 287, E1154–E1165.
Enyedi P, Braun G & Czirják G (2012). TRESK: the lone ranger of two-pore domain potassium
channels. Mol Cell Endocrinol 353, 75–81.
Enyedi P & Czirják G (2010). Molecular background of leak K+ currents: two-pore domain
potassium channels. Physiol Rev 90, 559–605.
Enyedi P, Veres I, Braun G & Czirják G (2014). Tubulin binds to the cytoplasmic loop of
TRESK background K+ channel in vitro. PloS One 9, e97854.
Es-Salah-Lamoureux Z, Steele DF & Fedida D (2010). Research into the therapeutic roles of
two-pore-domain potassium channels. Trends Pharmacol Sci 31, 587–595.
Feliciangeli S, Bendahhou S, Sandoz G, Gounon P, Reichold M, Warth R, Lazdunski M,
Barhanin J & Lesage F (2007). Does sumoylation control K2P1/TWIK1 background K+
channels? Cell 130, 563–569.
Feliciangeli S, Tardy MP, Sandoz G, Chatelain FC, Warth R, Barhanin J, Bendahhou S & Lesage
F (2010). Potassium channel silencing by constitutive endocytosis and intracellular sequestration.
J Biol Chem 285, 4798–4805.
Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C & Lazdunski M (1996). Cloning,
functional expression and brain localization of a novel unconventional outward rectifier K+
channel. EMBO J 15, 6854–6862.
Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M & Lazdunski M (1998). A
neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty
acids. EMBO J 17, 3297–3308.
Fong P, Argent BE, Guggino WB & Gray MA (2003). Characterization of vectorial chloride
transport pathways in the human pancreatic duct adenocarcinoma cell line HPAF. Am J Physiol
Cell Physiol 285, C433–C445.
Franks NP & Lieb WR (1988). Volatile general anaesthetics activate a novel neuronal K+ current.
Nature 333, 662–664.
Friedrich C, Rinné S, Zumhagen S, Kiper AK, Silbernagel N, Netter MF, Stallmeyer B, Schulze-

This article is protected by copyright. All rights reserved. 19
Bahr E & Decher N (2014). Gain-of-function mutation in TASK-4 channels and severe cardiac
conduction disorder. EMBO Mol Med 6, 937–951.
Garry A, Fromy B, Blondeau N, Henrion D, Brau F, Gounon P, Guy N, Heurteaux C,
Lazdunski M & Saumet JL (2007). Altered acetylcholine, bradykinin and cutaneous pressure-
induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link. EMBO
Rep 8, 354–359.
Gerstin KM, Gong DH, Abdallah M, Winegar BD, Eger EI & Gray AT (2003). Mutation of
KCNK5 or Kir3.2 potassium channels in mice does not change minimum alveolar anesthetic
concentration. Anesth Analg 96, 1345–1349, table of contents.
Gestreau C, Heitzmann D, Thomas J, Dubreuil V, Bandulik S, Reichold M, Bendahhou S,
Pierson P, Sterner C, Peyronnet-Roux J, Benfriha C, Tegtmeier I, Ehnes H, Georgieff M, Lesage
F, Brunet J-F, Goridis C, Warth R & Barhanin J (2010). Task2 potassium channels set central
respiratory CO2 and O2 sensitivity. Proc Natl Acad Sci U S A 107, 2325–2330.
Girard C, Duprat F, Terrenoire C, Tinel N, Fosset M, Romey G, Lazdunski M & Lesage F
(2001). Genomic and functional characteristics of novel human pancreatic 2P domain K(+)
channels. Biochem Biophys Res Commun 282, 249–256.
Girard C, Tinel N, Terrenoire C, Romey G, Lazdunski M & Borsotto M (2002). p11, an annexin
II subunit, an auxiliary protein associated with the background K+ channel, TASK-1. EMBO J
21, 4439–4448.
Goldstein SAN, Bayliss DA, Kim D, Lesage F, Plant LD & Rajan S (2005). International Union
of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels.
Pharmacol Rev 57, 527–540.
González C, Baez-Nieto D, Valencia I, Oyarzún I, Rojas P, Naranjo D & Latorre R (2012). K(+)
channels: function-structural overview. Compr Physiol 2, 2087–2149.
González JA, Jensen LT, Doyle SE, Miranda-Anaya M, Menaker M, Fugger L, Bayliss DA &
Burdakov D (2009). Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but
does not abolish glucose or pH responses of orexin/hypocretin neurons. Eur J Neurosci 30, 57–
64.
Gotter AL, Santarelli VP, Doran SM, Tannenbaum PL, Kraus RL, Rosahl TW, Meziane H,
Montial M, Reiss DR, Wessner K, McCampbell A, Stevens J, Brunner JI, Fox SV, Uebele VN,
Bayliss DA, Winrow CJ & Renger JJ (2011). TASK-3 as a potential antidepressant target. Brain
Res 1416, 69–79.
Gruss M, Mathie A, Lieb WR & Franks NP (2004). The two-pore-domain K(+) channels
TREK-1 and TASK-3 are differentially modulated by copper and zinc. Mol Pharmacol 66, 530–
537.
Gu W, Schlichthörl G, Hirsch JR, Engels H, Karschin C, Karschin A, Derst C, Steinlein OK &
Daut J (2002). Expression pattern and functional characteristics of two novel splice variants of
the two-pore-domain potassium channel TREK-2. J Physiol 539, 657–668.
Guagliardo NA, Yao J, Hu C, Schertz EM, Tyson DA, Carey RM, Bayliss DA & Barrett PQ
(2012). TASK-3 channel deletion in mice recapitulates low-renin essential hypertension.
Hypertension 59, 999–1005.
Gurney AM, Osipenko ON, MacMillan D, McFarlane KM, Tate RJ & Kempsill FEJ (2003).
Two-pore domain K channel, TASK-1, in pulmonary artery smooth muscle cells. Circ Res 93,
957–964.
Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA,
Rudy B, Sanguinetti MC, Stühmer W & Wang X (2005). International Union of Pharmacology.
LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol
Rev 57, 473–508.

This article is protected by copyright. All rights reserved. 20
Guyon A, Tardy MP, Rovère C, Nahon J-L, Barhanin J & Lesage F (2009). Glucose inhibition
persists in hypothalamic neurons lacking tandem-pore K+ channels. J Neurosci Off J Soc Neurosci
29, 2528–2533.
Hartness ME, Lewis A, Searle GJ, O’Kelly I, Peers C & Kemp PJ (2001). Combined antisense
and pharmacological approaches implicate hTASK as an airway O(2) sensing K(+) channel. J
Biol Chem 276, 26499–26508.
Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C, Schweda F, El Wakil A, Lalli E,
Guy N, Mengual R, Reichold M, Tegtmeier I, Bendahhou S, Gomez-Sanchez CE, Aller MI,
Wisden W, Weber A, Lesage F, Warth R & Barhanin J (2008). Invalidation of TASK1 potassium
channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. EMBO J 27, 179–
187.
Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L,
Widmann C, Zanzouri M, Romey G & Lazdunski M (2004). TREK-1, a K+ channel involved in
neuroprotection and general anesthesia. EMBO J 23, 2684–2695.
Heurteaux C, Lucas G, Guy N, El Yacoubi M, Thümmler S, Peng X-D, Noble F, Blondeau N,
Widmann C, Borsotto M, Gobbi G, Vaugeois J-M, Debonnel G & Lazdunski M (2006).
Deletion of the background potassium channel TREK-1 results in a depression-resistant
phenotype. Nat Neurosci 9, 1134–1141.
Honoré E, Maingret F, Lazdunski M & Patel AJ (2002). An intracellular proton sensor
commands lipid- and mechano-gating of the K(+) channel TREK-1. EMBO J 21, 2968–2976.
Hwang EM, Kim E, Yarishkin O, Woo DH, Han K-S, Park N, Bae Y, Woo J, Kim D, Park M,
Lee CJ & Park J-Y (2014). A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates
passive conductance in astrocytes. Nat Commun 5, 3227.
Kang D, Choe C, Cavanaugh E & Kim D (2007). Properties of single two-pore domain TREK-2
channels expressed in mammalian cells. J Physiol 583, 57–69.
Kang D, Choe C & Kim D (2005). Thermosensitivity of the two-pore domain K+ channels
TREK-2 and TRAAK. J Physiol 564, 103–116.
Kang D, Han J & Kim D (2006). Mechanism of inhibition of TREK-2 (K2P10.1) by the Gq-
coupled M3 muscarinic receptor. Am J Physiol Cell Physiol 291, C649–C656.
Kang D & Kim D (2004). Single-channel properties and pH sensitivity of two-pore domain K+
channels of the TALK family. Biochem Biophys Res Commun 315, 836–844.
Kang D, Kim E-J & Han J (2012). Direct Inhibitory Effect of Fluoxetine on TREK-2 Channel.
Biophys J 102, 680a.
Kemp PJ, Peers C, Lewis A & Miller P (2004). Regulation of recombinant human brain tandem
P domain K+ channels by hypoxia: a role for O2 in the control of neuronal excitability? J Cell
Mol Med 8, 38–44.
Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL & Mathie A (2005).
Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its
metabolite norfluoxetine. Br J Pharmacol 144, 821–829.
Kim D, Cavanaugh EJ, Kim I & Carroll JL (2009). Heteromeric TASK-1/TASK-3 is the major
oxygen-sensitive background K+ channel in rat carotid body glomus cells. J Physiol 587, 2963–
2975.
Kim D & Gnatenco C (2001). TASK-5, a new member of the tandem-pore K(+) channel family.
Biochem Biophys Res Commun 284, 923–930.
Kim D, Sladek CD, Aguado-Velasco C & Mathiasen JR (1995). Arachidonic acid activation of a
new family of K+ channels in cultured rat neuronal cells. J Physiol 484, 643–660.
Kim E, Hwang EM, Yarishkin O, Yoo JC, Kim D, Park N, Cho M, Lee YS, Sun C-H, Yi G-S,

This article is protected by copyright. All rights reserved. 21
Yoo J, Kang D, Han J, Hong S-G & Park J-Y (2010). Enhancement of TREK1 channel surface
expression by protein-protein interaction with beta-COP. Biochem Biophys Res Commun 395, 244–
250.
Kim Y, Bang H, Gnatenco C & Kim D (2001a). Synergistic interaction and the role of C-
terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali. Pflüg
Arch Eur J Physiol 442, 64–72.
Kim Y, Bang H & Kim D (2000). TASK-3, a new member of the tandem pore K(+) channel
family. J Biol Chem 275, 9340–9347.
Kim Y, Gnatenco C, Bang H & Kim D (2001b). Localization of TREK-2 K+ channel domains
that regulate channel kinetics and sensitivity to pressure, fatty acids and pHi. Pflüg Arch Eur J
Physiol 442, 952–960.
Koh SD, Monaghan K, Sergeant GP, Ro S, Walker RL, Sanders KM & Horowitz B (2001).
TREK-1 regulation by nitric oxide and cGMP-dependent protein kinase. An essential role in
smooth muscle inhibitory neurotransmission. J Biol Chem 276, 44338–44346.
Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG,
Seino S & Vandenberg CA (2005). International Union of Pharmacology. LIV. Nomenclature
and molecular relationships of inwardly rectifying potassium channels. Pharmacol Rev 57, 509–526.
Lafrenière RG, Cader MZ, Poulin J-F, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K,
Lafrenière F, McLaughlan S, Dubé M-P, Marcinkiewicz MM, Ramagopalan S, Ansorge O, Brais
B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G & Rouleau GA (2010). A
dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with
aura. Nat Med 16, 1157–1160.
Laigle C, Confort-Gouny S, Le Fur Y, Cozzone PJ & Viola A (2012). Deletion of TRAAK
potassium channel affects brain metabolism and protects against ischemia. PloS One 7, e53266.
Lauritzen I, Chemin J, Honoré E, Jodar M, Guy N, Lazdunski M & Jane Patel A (2005). Cross-
talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton. EMBO Rep 6,
642–648.
Lauritzen I, Zanzouri M, Honoré E, Duprat F, Ehrengruber MU, Lazdunski M & Patel AJ
(2003). K+-dependent Cerebellar Granule Neuron Apoptosis ROLE OF TASK LEAK K+
CHANNELS. J Biol Chem 278, 32068–32076.
Lesage F & Barhanin J (2011). Molecular Physiology of pH-Sensitive Background K2P Channels.
Physiology 26, 424–437.
Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G & Barhanin J (1996a).
TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure.
EMBO J 15, 1004–1011.
Lesage F, Maingret F & Lazdunski M (2000a). Cloning and expression of human TRAAK, a
polyunsaturated fatty acids-activated and mechano-sensitive K(+) channel. FEBS Lett 471, 137–
140.
Lesage F, Reyes R, Fink M, Duprat F, Guillemare E & Lazdunski M (1996b). Dimerization of
TWIK-1 K+ channel subunits via a disulfide bridge. EMBO J 15, 6400–6407.
Lesage F, Terrenoire C, Romey G & Lazdunski M (2000b). Human TREK2, a 2P domain
mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids,
lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J Biol Chem 275, 28398–28405.
L’Hoste S, Barriere H, Belfodil R, Rubera I, Duranton C, Tauc M, Poujeol C, Barhanin J &
Poujeol P (2007). Extracellular pH alkalinization by Cl-/HCO3- exchanger is crucial for TASK2
activation by hypotonic shock in proximal cell lines from mouse kidney. Am J Physiol Renal Physiol
292, F628–F638.

This article is protected by copyright. All rights reserved. 22
Li XT, Dyachenko V, Zuzarte M, Putzke C, Preisig-Müller R, Isenberg G & Daut J (2006). The
stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle. Cardiovasc Res 69,
86–97.
Liang B, Soka M, Christensen AH, Olesen MS, Larsen AP, Knop FK, Wang F, Nielsen JB,
Andersen MN, Humphreys D, Mann SA, Huttner IG, Vandenberg JI, Svendsen JH, Haunsø S,
Preiss T, Seebohm G, Olesen S-P, Schmitt N & Fatkin D (2014). Genetic variation in the two-
pore domain potassium channel, TASK-1, may contribute to an atrial substrate for
arrhythmogenesis. J Mol Cell Cardiol 67, 69–76.
Linden A-M, Aller MI, Leppä E, Vekovischeva O, Aitta-aho T, Veale EL, Mathie A, Rosenberg
P, Wisden W & Korpi ER (2006). The in Vivo Contributions of TASK-1-Containing Channels
to the Actions of Inhalation Anesthetics, the α2 Adrenergic Sedative Dexmedetomidine, and
Cannabinoid Agonists. J Pharmacol Exp Ther 317, 615–626.
Linden A-M, Sandu C, Aller MI, Vekovischeva OY, Rosenberg PH, Wisden W & Korpi ER
(2007). TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive
functions, and reduced sensitivity to inhalation anesthetics. J Pharmacol Exp Ther 323, 924–934.
Liu C, Au JD, Zou HL, Cotten JF & Yost CS (2004). Potent activation of the human tandem
pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesth Analg
99, 1715–1722, table of contents.
Lloyd EE, Crossland RF, Phillips SC, Marrelli SP, Reddy AK, Taffet GE, Hartley CJ & Bryan
RM (2011). Disruption of K2P6.1 Produces Vascular Dysfunction and Hypertension in Mice.
Hypertension 58, 672–678.
Lopes CMB, Rohács T, Czirják G, Balla T, Enyedi P & Logothetis DE (2005). PIP2 hydrolysis
underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+
channels. J Physiol 564, 117–129.
Lotshaw DP (2006). Biophysical and pharmacological characteristics of native two-pore domain
TASK channels in rat adrenal glomerulosa cells. J Membr Biol 210, 51–70.
Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M,
Trégouët D-A, Borczuk A, Rosenzweig EB, Girerd B, Montani D, Humbert M, Loyd JE, Kass
RS & Chung WK (2013). A novel channelopathy in pulmonary arterial hypertension. N Engl J
Med 369, 351–361.
Ma L, Zhang X & Chen H (2011). TWIK-1 two-pore domain potassium channels change ion
selectivity and conduct inward leak sodium currents in hypokalemia. Sci Signal 4, ra37.
Ma L, Zhang X, Zhou M & Chen H (2012). Acid-sensitive TWIK and TASK two-pore domain
potassium channels change ion selectivity and become permeable to sodium in extracellular
acidification. J Biol Chem 287, 37145–37153.
Maher BH, Taylor M, Stuart S, Okolicsanyi RK, Roy B, Sutherland HG, Haupt LM & Griffiths
LR (2013). Analysis of 3 common polymorphisms in the KCNK18 gene in an Australian
Migraine case-control cohort. Gene 528, 343–346.
Maingret F, Fosset M, Lesage F, Lazdunski M & Honoré E (1999a). TRAAK is a mammalian
neuronal mechano-gated K+ channel. J Biol Chem 274, 1381–1387.
Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M & Honoré E
(2000a). TREK-1 is a heat-activated background K(+) channel. EMBO J 19, 2483–2491.
Maingret F, Patel AJ, Lesage F, Lazdunski M & Honoré E (1999b). Mechano- or acid stimulation,
two interactive modes of activation of the TREK-1 potassium channel. J Biol Chem 274, 26691–
26696.
Maingret F, Patel AJ, Lesage F, Lazdunski M & Honoré E (2000b). Lysophospholipids open the
two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. J Biol Chem 275, 10128–
10133.

This article is protected by copyright. All rights reserved. 23
Mathie A, Al-Moubarak E & Veale EL (2010). Gating of two pore domain potassium channels. J
Physiol 588, 3149–3156.
Mazella J, Pétrault O, Lucas G, Deval E, Béraud-Dufour S, Gandin C, El-Yacoubi M, Widmann
C, Guyon A, Chevet E, Taouji S, Conductier G, Corinus A, Coppola T, Gobbi G, Nahon J-L,
Heurteaux C & Borsotto M (2010). Spadin, a sortilin-derived peptide, targeting rodent TREK-1
channels: a new concept in the antidepressant drug design. PLoS Biol 8, e1000355.
Meadows HJ & Randall AD (2001). Functional characterisation of human TASK-3, an acid-
sensitive two-pore domain potassium channel. Neuropharmacology 40, 551–559.
Millar ID, Taylor HC, Cooper GJ, Kibble JD, Barhanin J & Robson L (2006). Adaptive
downregulation of a quinidine-sensitive cation conductance in renal principal cells of TWIK-1
knockout mice. Pflüg Arch Eur J Physiol 453, 107–116.
Miller AN & Long SB (2012). Crystal structure of the human two-pore domain potassium
channel K2P1. Science 335, 432–436.
Moha Ou Maati H, Veyssiere J, Labbal F, Coppola T, Gandin C, Widmann C, Mazella J,
Heurteaux C & Borsotto M (2012). Spadin as a new antidepressant: absence of TREK-1-related
side effects. Neuropharmacology 62, 278–288.
Morton MJ, O’Connell AD, Sivaprasadarao A & Hunter M (2003). Determinants of pH sensing
in the two-pore domain K(+) channels TASK-1 and -2. Pflüg Arch Eur J Physiol 445, 577–583.
Mu D, Chen L, Zhang X, See L-H, Koch CM, Yen C, Tong JJ, Spiegel L, Nguyen KCQ, Servoss
A, Peng Y, Pei L, Marks JR, Lowe S, Hoey T, Jan LY, McCombie WR, Wigler MH & Powers S
(2003). Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene.
Cancer Cell 3, 297–302.
Mulkey DK, Talley EM, Stornetta RL, Siegel AR, West GH, Chen X, Sen N, Mistry AM,
Guyenet PG & Bayliss DA (2007). TASK channels determine pH sensitivity in select respiratory
neurons but do not contribute to central respiratory chemosensitivity. J Neurosci Off J Soc Neurosci
27, 14049–14058.
Murbartián J, Lei Q, Sando JJ & Bayliss DA (2005). Sequential phosphorylation mediates
receptor- and kinase-induced inhibition of TREK-1 background potassium channels. J Biol Chem
280, 30175–30184.
Nie X, Arrighi I, Kaissling B, Pfaff I, Mann J, Barhanin J & Vallon V (2005). Expression and
insights on function of potassium channel TWIK-1 in mouse kidney. Pflüg Arch Eur J Physiol 451,
479–488.
Niemeyer MI, Cid LP, Peña-Münzenmayer G & Sepúlveda FV (2010). Separate gating
mechanisms mediate the regulation of K2P potassium channel TASK-2 by intra- and
extracellular pH. J Biol Chem 285, 16467–16475.
Niemeyer MI, González-Nilo FD, Zúñiga L, González W, Cid LP & Sepúlveda FV (2006).
Gating of two-pore domain K+ channels by extracellular pH. Biochem Soc Trans 34, 899–902.
Niemeyer MI, González-Nilo FD, Zúñiga L, González W, Cid LP & Sepúlveda FV (2007).
Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+
channel. Proc Natl Acad Sci U S A 104, 666–671.
Noël J, Sandoz G & Lesage F (2011). Molecular regulations governing TREK and TRAAK
channel functions. Channels Austin Tex 5, 402–409.
Noël J, Zimmermann K, Busserolles J, Deval E, Alloui A, Diochot S, Guy N, Borsotto M, Reeh
P, Eschalier A & Lazdunski M (2009). The mechano-activated K+ channels TRAAK and
TREK-1 control both warm and cold perception. EMBO J 28, 1308–1318.
Nogueira EF, Gerry D, Mantero F, Mariniello B & Rainey WE (2010). The role of TASK1 in
aldosterone production and its expression in normal adrenal and aldosterone-producing
adenomas. Clin Endocrinol (Oxf) 73, 22–29.

This article is protected by copyright. All rights reserved. 24
O’Kelly I, Butler MH, Zilberberg N & Goldstein SAN (2002). Forward transport. 14-3-3 binding
overcomes retention in endoplasmic reticulum by dibasic signals. Cell 111, 577–588.
Ozaita A & Vega-Saenz de Miera E (2002). Cloning of two transcripts, HKT4.1a and HKT4.1b,
from the human two-pore K+ channel gene KCNK4. Chromosomal localization, tissue
distribution and functional expression. Brain Res Mol Brain Res 102, 18–27.
Pandit LM, Lloyd EE, Reynolds JO, Lawrence WS, Reynolds C, Wehrens XHT & Bryan RM
(2014). TWIK-2 Channel Deficiency Leads to Pulmonary Hypertension Through a Rho-Kinase-
Mediated Process. Hypertension; DOI: 10.1161/HYPERTENSIONAHA.114.03406.
Patel AJ, Honoré E, Lesage F, Fink M, Romey G & Lazdunski M (1999). Inhalational anesthetics
activate two-pore-domain background K+ channels. Nat Neurosci 2, 422–426.
Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F & Lazdunski M (1998). A
mammalian two pore domain mechano-gated S-like K+ channel. EMBO J 17, 4283–4290.
Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M & Honoré E (2000). TWIK-2, an
inactivating 2P domain K+ channel. J Biol Chem 275, 28722–28730.
Pei L, Wiser O, Slavin A, Mu D, Powers S, Jan LY & Hoey T (2003). Oncogenic potential of
TASK3 (Kcnk9) depends on K+ channel function. Proc Natl Acad Sci U S A 100, 7803–7807.
Penton D, Bandulik S, Schweda F, Haubs S, Tauber P, Reichold M, Cong LD, El Wakil A,
Budde T, Lesage F, Lalli E, Zennaro M-C, Warth R & Barhanin J (2012). Task3 potassium
channel gene invalidation causes low renin and salt-sensitive arterial hypertension. Endocrinology
153, 4740–4748.
Pereira V, Busserolles J, Christin M, Devilliers M, Poupon L, Legha W, Alloui A, Aissouni Y,
Bourinet E, Lesage F, Eschalier A, Lazdunski M & Noël J (2014). Role of the TREK2 potassium
channel in cold and warm thermosensation and in pain perception. Pain; DOI:
10.1016/j.pain.2014.09.013.
Piechotta PL, Rapedius M, Stansfeld PJ, Bollepalli MK, Erhlich G, Andres‐Enguix I,
Fritzenschaft H, Decher N, Sansom MSP, Tucker SJ & Baukrowitz T (2011). The pore structure
and gating mechanism of K2P channels. EMBO J 30, 3607–3619.
Plant LD, Zuniga L, Araki D, Marks JD & Goldstein SAN (2012). SUMOylation silences
heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule
neurons. Sci Signal 5, ra84.
Pountney DJ, Gulkarov I, Vega-Saenz de Miera E, Holmes D, Saganich M, Rudy B, Artman M
& Coetzee WA (1999). Identification and cloning of TWIK-originated similarity sequence
(TOSS): a novel human 2-pore K+ channel principal subunit. FEBS Lett 450, 191–196.
Premkumar LS, Gage PW & Chung S-H (1990). Coupled Potassium Channels Induced by
Arachidonic Acid in Cultured Neurons. Proc R Soc Lond B Biol Sci 242, 17–22.
Rahm A-K, Gierten J, Kisselbach J, Staudacher I, Staudacher K, Schweizer PA, Becker R, Katus
HA & Thomas D (2012). PKC-dependent activation of human K(2P) 18.1 K(+) channels. Br J
Pharmacol 166, 764–773.
Rajan S, Plant LD, Rabin ML, Butler MH & Goldstein SAN (2005). Sumoylation silences the
plasma membrane leak K+ channel K2P1. Cell 121, 37–47.
Rajan S, Wischmeyer E, Karschin C, Preisig-Müller R, Grzeschik KH, Daut J, Karschin A &
Derst C (2001). THIK-1 and THIK-2, a novel subfamily of tandem pore domain K+ channels. J
Biol Chem 276, 7302–7311.
Rajan S, Wischmeyer E, Xin Liu G, Preisig-Müller R, Daut J, Karschin A & Derst C (2000).
TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as
pH sensor. J Biol Chem 275, 16650–16657.
Renigunta V, Fischer T, Zuzarte M, Kling S, Zou X, Siebert K, Limberg MM, Rinné S, Decher

This article is protected by copyright. All rights reserved. 25
N, Schlichthörl G & Daut J (2014a). Cooperative endocytosis of the endosomal SNARE protein
syntaxin-8 and the potassium channel TASK-1. Mol Biol Cell 25, 1877–1891.
Renigunta V, Yuan H, Zuzarte M, Rinné S, Koch A, Wischmeyer E, Schlichthörl G, Gao Y,
Karschin A, Jacob R, Schwappach B, Daut J & Preisig-Müller R (2006). The retention factor p11
confers an endoplasmic reticulum-localization signal to the potassium channel TASK-1. Traffic
Cph Den 7, 168–181.
Renigunta V, Zou X, Kling S, Schlichthörl G & Daut J (2014b). Breaking the silence: functional
expression of the two-pore-domain potassium channel THIK-2. Pflüg Arch Eur J Physiol 466,
1735–1745.
Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N & Lazdunski M (1998). Cloning and
expression of a novel pH-sensitive two pore domain K+ channel from human kidney. J Biol
Chem 273, 30863–30869.
Rinné S, Renigunta V, Schlichthörl G, Zuzarte M, Bittner S, Meuth SG, Decher N, Daut J &
Preisig-Müller R (2014). A splice variant of the two-pore domain potassium channel TREK-1
with only one pore domain reduces the surface expression of full-length TREK-1 channels. Pflüg
Arch Eur J Physiol 466, 1559–1570.
Rodrigues N, Bennis K, Vivier D, Pereira V, C Chatelain F, Chapuy E, Deokar H, Busserolles J,
Lesage F, Eschalier A & Ducki S (2014). Synthesis and structure-activity relationship study of
substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel. Eur J Med
Chem 75, 391–402.
Sabbadini M & Yost CS (2009). Molecular biology of background K channels: insights from
K(2P) knockout mice. J Mol Biol 385, 1331–1344.
Sackin H (1995). Mechanosensitive channels. Annu Rev Physiol 57, 333–353.
Salinas M, Reyes R, Lesage F, Fosset M, Heurteaux C, Romey G & Lazdunski M (1999). Cloning
of a new mouse two-P domain channel subunit and a human homologue with a unique pore
structure. J Biol Chem 274, 11751–11760.
Sandoz G, Douguet D, Chatelain F, Lazdunski M & Lesage F (2009). Extracellular acidification
exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved
histidine residue. Proc Natl Acad Sci U S A 106, 14628–14633.
Sandoz G, Tardy MP, Thümmler S, Feliciangeli S, Lazdunski M & Lesage F (2008). Mtap2 is a
constituent of the protein network that regulates twik-related K+ channel expression and
trafficking. J Neurosci Off J Soc Neurosci 28, 8545–8552.
Sandoz G, Thümmler S, Duprat F, Feliciangeli S, Vinh J, Escoubas P, Guy N, Lazdunski M &
Lesage F (2006). AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive
TREK K(+) channels into open leak channels. EMBO J 25, 5864–5872.
Sano Y, Inamura K, Miyake A, Mochizuki S, Kitada C, Yokoi H, Nozawa K, Okada H,
Matsushime H & Furuichi K (2003). A novel two-pore domain K+ channel, TRESK, is localized
in the spinal cord. J Biol Chem 278, 27406–27412.
Simkin D, Cavanaugh EJ & Kim D (2008). Control of the single channel conductance of
K2P10.1 (TREK-2) by the amino-terminus: role of alternative translation initiation. J Physiol 586,
5651–5663.
Talley EM & Bayliss DA (2002). Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9)
potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action. J
Biol Chem 277, 17733–17742.
Thomas D, Plant LD, Wilkens CM, McCrossan ZA & Goldstein SAN (2008). Alternative
translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron
58, 859–870.
Tulleuda A, Cokic B, Callejo G, Saiani B, Serra J & Gasull X (2011). TRESK channel

This article is protected by copyright. All rights reserved. 26
contribution to nociceptive sensory neurons excitability: modulation by nerve injury. Mol Pain 7,
30.
Veale EL, Hassan M, Walsh Y, Al-Moubarak E & Mathie A (2014). Recovery of current through
mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol Pharmacol 85, 397–407.
Veale EL, Rees KA, Mathie A & Trapp S (2010). Dominant negative effects of a non-conducting
TREK1 splice variant expressed in brain. J Biol Chem 285, 29295–29304.
Voloshyna I, Besana A, Castillo M, Matos T, Weinstein IB, Mansukhani M, Robinson RB,
Cordon-Cardo C & Feinmark SJ (2008). TREK-1 is a novel molecular target in prostate cancer.
Cancer Res 68, 1197–1203.
Wang W, Putra A, Schools GP, Ma B, Chen H, Kaczmarek LK, Barhanin J, Lesage F & Zhou M
(2013). The contribution of TWIK-1 channels to astrocyte K(+) current is limited by retention in
intracellular compartments. Front Cell Neurosci 7, 246.
Warth R, Barrière H, Meneton P, Bloch M, Thomas J, Tauc M, Heitzmann D, Romeo E, Verrey
F, Mengual R, Guy N, Bendahhou S, Lesage F, Poujeol P & Barhanin J (2004). Proximal renal
tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing
bicarbonate transport. Proc Natl Acad Sci U S A 101, 8215–8220.
Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S & Wulff H (2005). International
Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated
potassium channels. Pharmacol Rev 57, 463–472.
Williams S, Bateman A & O’Kelly I (2013). Altered expression of two-pore domain potassium
(K2P) channels in cancer. PloS One 8, e74589.
Yost CS, Oh I, Eger EI & Sonner JM (2008). Knockout of the gene encoding the K(2P) channel
KCNK7 does not alter volatile anesthetic sensitivity. Behav Brain Res 193, 192–196.
Zuzarte M, Heusser K, Renigunta V, Schlichthörl G, Rinné S, Wischmeyer E, Daut J,
Schwappach B & Preisig-Müller R (2009). Intracellular traffic of the K+ channels TASK-1 and
TASK-3: role of N- and C-terminal sorting signals and interaction with 14-3-3 proteins. J Physiol
587, 929–952.