Content uploaded by Akinwunmi Adeoye
Author content
All content in this area was uploaded by Akinwunmi Adeoye on Apr 27, 2021
Content may be subject to copyright.
https://biointerfaceresearch.com/
690
Review
Volume 12, Issue 1, 2022, 690 - 705
https://doi.org/10.33263/BRIAC121.690705
Structure and Function of Aquaporins: the Membrane
Water Channel Proteins
Akinwunmi Adeoye 1,* , Atinuke Odugbemi 1, Tolulope Ajewole 2,*
1 Department of Biochemistry, Federal University Oye-Ekiti, Nigeria; akinwunmi.adeoye@fuoye.edu.ng (A.A.);
atinuke.odugbemi@gmail.com (A.O.);
2 Department of Plant Science and Biotechnology, Federal University Oye-Ekiti, Nigeria; tolu.ajewole@gmail.com (T.A.);
* Correspondence: akinwunmi.adeoye@fuoye.edu.ng (A.A.); tolu.ajewole@gmail.com (T.A.);
Scopus Author ID 57189907371
Received: 5.03.2021; Revised: 18.04.2021; Accepted: 21.04.2021; Published: 26.04.2021
Abstract: Aquaporins are integral membrane proteins which are also known as water channel proteins.
They aid quick transportation of water across membranes and are important in controlling cell volume
and transcellular water passage. Aquaporins are present in organisms, and they vary from archaea and
bacteria to plants and animals. They are also found in insects and yeast. Presently, 13 mammalian
aquaporins (AQP0 to AQP12) have been cloned and identified in every tissue in the body. These
aquaporins are alike in basic structure with monomers containing six transmembrane and two short
helical segments that enclose cytoplasmic and extracellular vestibules linked by aqueous pore. They
have distinctive structures that define their functions, mode of action, and even their various control
methods. Phylogenetic analysis of aquaporin consists of aquaporins, glycerol facilitators, plasma
membrane integral proteins of plants, tonoplast integral proteins of plants, nodules of plants, and
AQP8s. Aquaporins are structurally related due to their great similarity in their structural regions,
mainly in the pore-forming domains, which accounts for the similarity in their transport mechanisms.
The water movement by AQPs is controlled by a change in conformation or by modifying the AQP
density in the membrane and at the transcriptional and translational levels. Aquaporins are important in
several physiological processes and are also linked with several clinical disorders, such as brain edema,
loss of vision, and kidney dysfunction.
Keywords: aquaporins; water channel; membrane proteins; transport; permeability.
© 2021 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
1. Introduction
Aquaporins belong to integral membrane proteins that form pores in the biological cell
membrane and are essential for facilitating water transport between cells [1]. The importance
of water cannot be overemphasized, which results in its abundance in living cells. Aquaporins
are also known as water channel proteins. Since the discovery of the first aquaporin (AQP1) in
mammals, many aquaporins have been found and classified in microorganisms, plants, and
animals [2-4]. Thirteen (13) mammalian Aquaporins, AQP0 to AQP12, have been cloned and
identified in every tissue in the body. They differ in size with diverse water permeability. The
channel-forming integral protein (CHIP28), known as a major erythrocyte plasma membrane
protein, was reported to be the first protein identified with a water transport activity. As the
first example of the water channel protein, the nomenclature CHIP28 was changed to AQP1[5].
Aquaporins (AQPs) are known to be water channel proteins that exhibit numerous
functional properties in plant growth and development, such as uptake of uncharged solute,
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
691
stress response, control of cell volume, and transcellular water passage. Aquaporins conduct
water at a rate of 109 molecules per second, which is almost comparable to the free diffusion
of water [6].
Aquaporin provides a proteinaceous pathway for water. They are of a similar basic
structure, consisting of a narrow aqueous pore that is connected to the cytoplasmic and
extracellular vestibules surrounded by aquaporin monomers containing six transmembrane and
two short helical segments. The short helical segments have several conserved motifs and Asn-
Pro-Ala (NPA) sequences [7].
Mammalian aquaporins are expressed in different organs such as the brain, kidney, lens,
lungs, and also in cell types implicated in fluid transport such as eye, gastrointestinal organs,
etc. However, it has been reported that cells with no obvious role in fluid transport also
expressed aquaporins. Examples of these cells are erythrocytes and some leukocytes,
adipocytes, and skeletal muscle. Other cells that express aquaporins include astrocytes,
supportive cells, and sensory organs [7]. In plants, aquaporins are known to contribute to a
range of physiological processes such as photosynthesis. They are also known to play a role in
the pathophysiology in various clinical conditions such as diabetes insipidus and edema and
could target therapy in altered water homeostasis diseases [8].
About eleven (11) different aquaporin types are found in different parts of the human
body. Multiple water-channel homologs are expressed in the kidney, lung, eye, and brain,
which provide an arrangement for water transport in those locations. AQP1, 3, 5, 7, 9, and 10
are expressed in the human skin, but only AQPs of the sweat and sebaceous glands and
epidermis are strictly related to skin physiology. AQP5 functions as water secretion in sweat
glands[9]. AQP3 is expressed in keratinocytes, and it is important in the transport and
metabolism of glycerol in mouse skin epidermis [10].
The digestive system's major function is secretion and absorption, which requires the
transport of fluid across cellular membranes[11]. AQP1 is expressed in the digestive system
along the apical, basolateral membranes and an endothelial cell which is responsible for
transendothelial water transport [12]. Aquaporin 3 is expressed in the epithelial lining [13],
while both AQP3 and 4 are expressed in the gastrointestinal tract [14]. AQP8 is expressed in
the apical plasma membrane of pancreatic duct cells[15], while AQP9 is found in the liver
hepatocytes [16].
Cell membranes' porosity to water and hormones in both the male and female
reproductive systems is vital for folliculogenesis [17], spermatogenesis, and sperm osmo-
adaptation [18]. AQPs are found to be linked with the pathogenesis of several reproductive
disorders such as polycystic ovary syndrome[19].
Aquaporin families in plants are complex and are made up of a great number of genes.
For instance, about 35 AQPs are found in Arabidopsis thaliana, 34 in Oryza sativa,31 in Zea
mays, etc. [20]. AQPs play a key role in water and solute transport and maintain water
homeostasis in response to environmental stresses. The roles of aquaporins in glycerol, boric
acid, urea, NH3, and CO transport via cell membranes are also essential for seed germination,
cytoplasm homeostasis, petal and leaf movement, maintenance of cell turgor under various
stresses, and fruit ripening [2]. Several uncharged solutes or gases such as urea, ammonia,
carbon dioxide (CO2), hydrogen peroxide (H2O2), nitric oxide (NO), etc., are reported to cross
the cellular membrane via aquaporin channels [21].
Aquaporins have been characterized into seven subfamilies: small basic intrinsic
proteins (SIPs), plasma membrane intrinsic proteins, x-intrinsic proteins, h-intrinsic proteins,
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
692
intrinsic glycerol proteins,nodulin-like plasma membrane intrinsic proteins, and tonoplast
intrinsic proteins [22, 23].
2. Structure of Aquaporins
Aquaporins are expressed generally throughout the plant and animal kingdoms. They
are alike in basic structure, with monomers containing six transmembrane and two short helical
segments that enclose cytoplasmic and extracellular vestibules linked by aqueous pore [7].
They have several conserved motifs in their short helical segments as well as NPA sequences.
Aquaporin monomers form tetramers in membranes, and each monomer forms functional water
more independently. The tetrameric structure is common to all the AQP family. Some
aquaporins, such as mammalian AQP4, can further be combined in cell membranes to form
assemblies of a supramolecular crystalline structure called orthogonal arrays of particles [7].
The six transmembrane α-helical protein domains in the membrane plane form a barrel-
like configuration. The amino and carboxy-terminal domains are responsible for the specific
regulation of aquaporin activity. The cytoplasmic loops and the periplasmic loops are made up
of two short α-helical domains on the opposite sides of the barrel, which are said to contribute
to the water channel's formation. The domains are situated close to each other in the molecule.
Each domain is made up of the NPA (Asn-Pro-Ala) motif, which is conserved for all aquaporins
[24]. The structure is regarded as the ‘hourglass model’ [25]. The ‘hourglass model’ structure
was established as three-dimensional maps of AQP1 through cryoelectron microscopy. The
structure showed that aquaporins contain tetrameric subunits placed in parallel, forming a fifth
pore in the tetramer center [26]. When incorporated into the membrane, aquaporins generate
homotetramers [27]. The tetramer's assemblage is essential for appropriate folding and stability
of protein, sorting, and posttranslational modifications of proteins. Each of the four subunits
produces an independent water channel in the complex, whereas the pore is oriented along the
tetramer axis [28, 29].The quaternary structure of the water channel is at variance in stability
for various phylogenetic clusters of aquaporins. The tetramers of aquaporins with glycerol
specificity are less stable [30].
The passage of water along the pore in a thermodynamically favorable condition is
provided by forming new hydrogen bonds between the water molecule and aquaporin atoms.
The binding to the protein occurs due to the oxygen atoms of the peptide groups from a number
of sequential amino-acid residues [31]. The chains have both cytoplasmic and external surfaces
which project towards the pore center. The chains are formed by amino acids of the loops
containing two short α-helical domains. The protein molecule has at the center two NPA motifs
with closely positioned asparagine residues that form the middle pore region. The amide groups
of these residues also form hydrophilic areas over the channel surface. The transport of water
molecules from one asparagine residue to another causes a release of molecules from a
continuous hydrogen bond system formed as a result of water movement along the water pore
[32].
3. Family of Aquaporins
Aquaporins are made up of a family of water-transporting membrane proteins. Members
of the AQP family are divided into two subfamilies based on their permeability
characteristics:
(i) Classic AQPs (water selective) which conduct water exclusively;
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
693
(ii) Aquaglyceroporins possess the extended ability to conduct small linear carbohydrates,
in particular, glycerol, a metabolic intermediate [33];
Based on the functions of aquaporins, they are classified into three subfamilies:
(a) Those that are selectively permeable for water. They are also known as orthodox
aquaporins, which includes AQP1, 2, 4 and 5;
(b)Those that are permeable to water as well as to glycerol, urea, and/or other small solutes;
They are also known as aquaglyceroporins which include AQP3, 7, 9 and 10; and
(c) Unorthodox aquaporins, which include AQP6, 8, 11, and 12;
Thirteen (13) aquaporins subtypes have been identified recently, and their distribution
in various tissues is linked to their functional roles in water-transporting [34]. More so,
aquaporins may also be classified into five categories; classical aquaporins, unorthodox
aquaporins, AQP8- type aquaammoniaporins, plasma membrane intrinsic, and
aquaglyceroporins, according to the phylogenetic tree or phylogenetic topology as inferred
from Bayesian inference.
3.1. Aquaporin 0.
The mRNA encoding AQP0 was initially identified in 1984 [35], and it was believed
to be an aqueous channel and/or a gap junctional protein. It was referred to as MIP- major
intrinsic protein of the lens. However, following the discovery of AQP1 and developing the
functional assays for water transporters, it was renamed AQP0 [36]. This channel transports
water at a slower rate than that of AQP1 [37], and in addition to facilitating water, AQP0 has
been reported to play a role in the cell-to-cell adhesion of the lens fiber. Studies have shown
that human individuals with mutations in AQP0 suffer from cataracts, a symptom ranging from
cloudy vision to blindness [38].
3.2. Aquaporin 1.
AQP1 is the most studied aquaporins. It was reported as the first protein for which water
transport was measured, and a high-resolution structure was determined [39]. Studies have
identified a clear gating mechanism of action of AQP1 and that alteration of osmotic conditions
could induce a reversible protein kinase C (PKC) dependent change in the membrane
localization of AQP1 [40], which suggests a regulatory mechanism by trafficking. The protein
is found in many different tissues in the body, including red blood cells, kidneys, and lungs.
Mice and humans lacking AQP1 have shown to have urinary concentration deficiency during
water deprivation [41].
3.3. Aquaporin 2.
AQP2 was discovered shortly after AQP1. It was found in the renal collecting duct and
hence called the water channel of the collecting duct (WCH-CD) [42]. The trafficking of AQP2
is one of the most studied aquaporin regulation mechanisms. Vasopressin triggers cAMP
signaling, leading to activation of protein kinase A, which phosphorylates AQP2 resulting in
translocation to the apical plasma membrane [43]. A mutation in AQP2 causes nephrogenic
diabetes insipidus [44], and mice with mutations in this gene show severe urine concentration
defects [45].
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
694
3.4. Aquaporin 3.
AQP3 was first identified in the basolateral membrane of the collecting duct in the
kidney[46]. It was named glycerol intrinsic protein (GLIP) or AQP3.In addition to water
transportation, AQP3 could also transport glycerol and urea. Aquaglyceroporin AQP3 was
found to be aberrantly expressed in various human cancers, including human skin cell
carcinomas and melanoma [47]. It is abundant in keratinocytes in the basal layer of the
epidermis in human skin [48]. Low pH and nickel concentrations could bring about inhibition
of AQP3 [49].AQP2 is reported to be down-regulated in AQP3 null mice, causing deficiency
in urine concentration and nephrogenic diabetes insipidus [50].
3.5. Aquaporin 4.
AQP4 was first cloned from rat lung [51] and rat brain [52] and was named mercurial
insensitive water channel (MIWC) due to the lack of mercury inhibition. Isoforms of AQP4
were identified in the brain and were shown to possess several amino acids and are reported to
transport water at higher rates [53]. There are two human isoforms; AQP4-M, a full-length
protein, and hAQP4-M23, which is the shorter, lacking the first 22 amino acids. [54]. AQP4
plays a major role in the control of water balance in the brain. A high-resolution structure of
truncated hAQP4 has also been reported with some differences in the interaction with waters
along the channel, as compared to other water-selective AQPs [55].
3.6. Aquaporin 5.
Aquaporin 5 is one of three human aquaporins with a known structure [56]. AQP5 was
first identified from a rat salivary gland, sweat glands, eyes, and lungs [57]. In the lungs, AQP5
is found in the submucosal glands' secretory cells [58, 59]. Studies have shown reduced
secretion of AQP5 in the sweat gland[60]. However, this observation is contrary to another
report[61]. Human AQP5 was found in salivary glands' apical membrane, but it was primarily
located in patients' basal membranes with Sjögren’s syndrome [62]. Defective hAQP5
trafficking causes dry mouth and dry eyes, typical symptoms of patients suffering from
Sjögren’s syndrome. Moreover, AQP5 null mice have a major reduction in saliva production
[63]. In contrast, reports are indicating that the tear secretion is independent of any aquaporin
[64].
3.7. Aquaporin 6.
AQP6 was first cloned from rat kidneys and was initially referred to as water channel
3(WCH3). AQP6 was found to aid the transport of anions. A human AQP6 variant with a
slightly different sequence was also identified and referred to as hKID [46]. In contrast to other
aquaporins located in the kidney, AQP6 was found to be located in intracellular vesicles,
making it less likely to be involved in the reabsorption of water. AQP6 functions as an acid-
base regulator, with pH being the activating mechanism [65].
3.8. Aquaporin 7.
AQP7 was first cloned from rat testis [66] and was found to transport glycerol through
aquaglyceroporin with a high affinity for glycerol [67-69]. However, in humans, it was first
detected in adipose tissue [70], giving it the initial name AQP adipose (AQPap). The role in
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
695
this tissue is to provide the glycerol needed for gluconeogenesis [71]. AQP7 has also been
found to reabsorb glycerol in the kidney [72].
3.9. Aquaporin 8.
AQP8 was found in different tissues such as the colon, placenta, liver, heart [73], testis
[66], and pancreas [74]. In rat liver cells, AQP8 was observed to be trafficked from intracellular
vesicles to the plasma membrane in response to cAMP [75].
3.10. Aquaporin 9.
AQP9 was first identified in human white blood cells, where it was found to transport
water and urea but not glycerol [76]. Roles of AQP9 include facilitating glycerol uptake in the
liver [77] and acting as a glucose metabolite channel in the brain [78].
3.11. Aquaporin 10.
AQP10 is an aquaglyceroporin expressed only in the human gastrointestinal tract but
not in the mouse small intestine, where it has been demonstrated to be a pseudogene. AQP10
has been reported to transport water, glycerol, and urea when expressed in Xenopus oocytes
[79].
3.12. Aquaporin 11.
AQP11 is a 271-amino-acid protein in which the second NPA motifs are conserved, but
the first motif is substituted by NPC(Asn-Pro-Cys) in both mice and humans [34].In
immunohistochemical studies, AQP11 has been found in intracellular compartments of
proximal kidney tubes [80].
3.13. Aquaporin 12.
AQP12 was found by searching for homologs to AQP11. The protein was localized
intracellularly in the pancreas. AQP-12 is a 290- or 295-amino-acid aquaporin that is closely
related to AQP-8 in humans and to AQP-0 and AQP-6in mice [81]. The first NPA motif in
AQP-12 is substituted by an NPT (Asn-Pro-Thr) motif in both species.
4. Mechanism of Action of Aquaporin
A similar transport mechanism can be assumed for all aquaporins because they are
structurally related and have highly similar consensus regions, most especially in the pore-
forming domains. The hydrophobic domain has been suggested to be involved in substrate
specificity and/or size restriction. The aquaporin monomer's pathway is lined with conserved
hydrophobic residues that permit rapid water transport in the form of a single-file hydrogen-
bonded chain of water molecules[30].
The pore has two constriction sites: an aromatic region which is made up of a conserved
arginine residue (Arg195) forms the narrowest part of the pore[82], and the highly conserved
NPA motifs form a second filter, where single water molecules interact with the two asparagine
side chains[30]. The dipolar water molecule rotates 180 degrees during the passage via the
pore. The two filter regions build up electrostatic barriers, which prevent the permeation of
protons as a result of direct interaction between water molecules and the NPA motifs [82].
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
696
The water permeability and selectivity of aquaporins vary considerably. The water
permeabilities for human aquaporins have been estimated to be between 0.25 x 10-14 cm3/sec
for AQP0 and 24 x 10-14 cm3/sec for AQP4 [83].
Plant plasma-membrane aquaporins have aquaporin activity at different levels [84].
Plasma membrane intrinsic proteins (PIP1 and PIP2) isoforms from maize due to coexpression
and heteromerization induced an increase in permeability than the expression of single
isoforms [85]. Heteromerization seems to be important in heterologous expression systems and
the plant, as was revealed by analysis of PIP1 and PIP2 antisense Arabidopsis plants[86].
The mechanism by which aquaglyceroporins promote glycerol transport has been
investigated for the E. coli glycerol facilitator GlpF [87]. It was reported that the protein also
has conserved NPA motifs at similar positions to those in the water-selective aquaporins, but
aromatic amino acids achieve the preference for glycerol at the periplasmic side [87].
5. Regulation of Aquaporins
AQPs mediate the bidirectional water flow driven by an osmotic gradient. The transport
of water-mediated by AQPs is regulated either by gating, conformational change, or altering
the AQP density in a particular membrane. The trafficking of AQPs is regulated at the
transcriptional and/or translational level and involves shuttles of AQPs between intracellular
storage vesicles and the target membrane. The regulation of AQPs, either through gating or
trafficking, allow for rapid and specific regulation in a tissue-dependent manner. Another
relatively long-term regulation by which increased/decreased protein abundance of AQPs is
affected is by systemic hormones (e.g., vasopressin, insulin, angiotensin II), local molecules
(e.g., purine, prostaglandins, bradykinin, dopamine, and other common microenvironment
signals, including pH, divalent cation concentrations and osmolality [88].
The regulations of AQPs are often associated with certain physiological or
pathophysiological conditions. The cellular functions of aquaporins are regulated by
posttranslational modifications, e.g., phosphorylation, ubiquitination, glycosylation,
subcellular distribution, degradation, and protein interactions [89]. AQPs are consequently
expressed in bronchopulmonary tissues and are regulated to facilitate transcellular water
transport [90].
In plants and yeast, the plasma membrane-localized AQPs are gated in response to
environmental stress [50]. In mammals, gating regulates the water permeability of AQP0 in a
pH-dependent and Ca2+-calmodulin-dependent manner. The water transport via AQP0 is
regulated by C-terminal cleavage, pH, and Ca2+/calmodulin (CaM).
6. Regulation of Different Aquaporin Activity
Cyclic nucleotide and protein kinase pathways are the two regulatory mechanisms
currently proposed to be involved in the activation of AQP1 channel activity. Cyclic
nucleotides such as cAMP are known for their role as second messengers in both hormone and
ion-channel signaling in eukaryotic cells either directly or via activation of protein kinases and
subsequent phosphorylation of substrate proteins. It has been demonstrated that cAMP
increased the membrane permeability of water in Xenopus oocytes injected with AQP1 [91].
AQP2 is regulated by trafficking between intracellular storage vesicles and the apical
membrane, a process that is tightly controlled by the pituitary hormone vasopressin. The
signaling transduction pathways ensuing in the AQP2 trafficking to the apical plasma
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
697
membrane of the collecting duct principal cells and the changes to AQP2 abundance in times
of water-balance disorders have been studied extensively. AQP2 plays a key role in short-term
regulation and long-term adaptation to collect duct water permeability [92].
Short-term regulation is the process by which vasopressin quickly increases water
permeability of the collecting duct principal cells by stimulating vasopressin 2receptor (V2R)
in the basolateral plasma membrane and translocation of AQP2 from intracellular vesicles to
the apical plasma membrane [93].
Long-term adaptation of collecting duct water permeability ensue when circulating
vasopressin levels are raised over a period of hours to days, leading to an increase in AQP2
abundance per cell in the collecting ducts[94]. Studies have also demonstrated that
ubiquitination and subsequent proteasomal and/or lysosomal degradation of AQP2 could play
a critical role in regulating AQP2 abundance [95].
The expression of AQP3 could be regulated by the Ah Receptor (AhR), which, in turn,
is activated by numerous exogenous and endogenous ligands. AhRis triggered in response to
environmental pollutants, and it has been shown to regulate several cellular processes,
including cell migration and plasticity [96, 97].
AQP5 expression has been reported to be regulated by osmolality. It was suggested that
an osmotic gradient between a cell and its environment is involved in regulating AQP5
expression [81]. AQP5 expression is reported to be regulated by a cyclic AMP/protein kinase
A (cAMP/PKA)-dependent pathway [98].
7. Functions of Aquaporins
Most aquaporins' primary function is to transport water across cell membranes in
response to osmotic gradients created by active solute transport. Non-transporting functions for
some aquaporins have also been suggested, such as cell-cell adhesion, membrane polarization,
and regulation of interacting proteins, such as ion channels [7]. In injury conditions, AQPs
enhance short-term vulnerability to pathological volume changes and promote edema
formation [99].
AQPs have various known physiological roles; urine concentration in kidney tubules,
epithelial fluid secretion of saliva, cerebrospinal fluid, and aqueous humor production, cell
migration required for angiogenesis and wound healing, regulation of brain water homeostasis,
neural signal transduction, skin moisturization, cell proliferation in wound healing and fat
metabolism.
AQPs function as components of the vital cellular apparatus to maintain the
physiological homeostasis of the musculoskeletal system. Several AQP family members are
expressed within the epididymis of the male reproductive tract [100]. They are localized to the
epithelial layer and are thought to play an important role in transepithelial water transport and
sperm concentration [100]. Evidence has shown that AQPs play an important role in the
maintenance of the structure and function of sperm and thus male fertility[101].
AQP0 is the protein in the eye lens's fiber cells, where it is required for homeostasis
and transparency of the lens [102-106]. AQP1 water channel blockers, as earlier reported, could
be potent anti-brain tumor edema agents [107]. AQP1 is expressed in choroid plexus epithelium
and may be important in forming cerebrospinal fluid [108]. AQP2 is the vasopressin-regulated
water-channel protein found at the connecting tubule and collecting duct and plays a crucial
role in urine concentration and body-water homeostasis[109]. AQP3 is the most abundant skin
aquaglyceroporin, facilitates water and glycerol transport, and plays a major role in the
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
698
hydration of mammalian skin epidermis and proliferation and differentiation of keratinocytes
[110]. One of the mechanisms proposed to explain AQP3 participation in tumor growth and
spread is the ability to transport H2O2, thereby modulating oxidative stress and triggering
signaling cascades responsible for cell proliferation and migration [111, 112]. AQP3 may
mediate the reabsorption of water from feces by transporting it from the lumen across the
endothelial layer into the blood vessels via AQP1 [113].
AQP4 is involved in diverse functions such as regulation of extracellular space volume,
potassium buffering, cerebrospinal fluid circulation, waste clearance, neuroinflammation,
osmosensation, cell migration, and Ca2+ signaling [114]. AQP4 regulates transcellular water
flow in cerebral edema [101].AQP5 is expressed in glandular epithelia, alveolar epithelium,
and secretory glands, where it is involved in the generation of saliva, tears, and pulmonary
secretions. AQP5 is also found at the plasma membrane in the stratum granulosum and reported
to play a role in transcellular water homeostasis in the skin [115].
AQP3 and AQP5 were found to be abnormally expressed in quite a number of human
tumors and have been considered potential therapeutic targets and biomarkers with prognostic
value[116].
AQP6 enables the transport of urea, glycerol, nitrate [117], and AQP7 facilitates water,
glycerol, urea, ammonia, and arsenite [107].
AQP8 has been reported to facilitate hydrogen peroxide diffusion across mitochondrial
membranes in situations when reactive oxygen species are generated [39]. AQP9 is expressed
at the sinusoidal plasma membrane of hepatocytes [118], where it serves as a conduit for the
uptake of ammonia and mediates the efflux of newly synthesized urea. AQP9 could also
function as a glycerol channel to facilitate glycerol uptake in the liver. AQP10 and AQP7 are
important for maintaining normal or low glycerol contents inside the adipocyte, thus protecting
humans from obesity [119]. AQP12 functions in controlling the proper secretion of pancreatic
fluid following rapid and intense stimulation.
8. Conclusions
Since the first aquaporin description, much information on the physiological
significance of these channel proteins has accumulated. Water channels have been identified
in almost every living organism, from plants to animals, from prokaryotes to eukaryotes,
including humans. Water regulation is crucially important for every cell and, therefore, for all
life forms on earth. Structural features, such as the right-handed helical bundle and the mostly
hydrophobic pore, were revealed by electron crystallography. While all AQPs share the same
basic fold, the subtle differences between the different AQPsprovided most of the insights.
Structural and dynamic information on the atomic scale is a prerequisite to understanding the
function of a channel, and this information could become the basis for designing novel
therapeutics for various diseases related to water balance perturbation.
Funding
This research received no external funding.
Acknowledgments
This research has no acknowledgment.
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
699
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Agre, P. The aquaporin water channels. Proc Am Thorac Soc 2006, 3, 5-
13.https://doi.org/10.1513/pats.200510-109JH.
2. Kong, W.; Yang, S.; Wang, Y.; Bendahmane, M.; Fu, X. Genome-wide identification and characterization of
aquaporin gene family in Beta vulgaris. Peer J. 2017, 5, e3747. https://doi.org/10.7717/peerj.3747.
3. Nesverova, V.; Tornroth-Horsefield, S. Phosphorylation-dependent regulation of mammalian aquaporins.
Cells 2019, 8,82. https://doi.org/10.3390/cells8020082
4. Zhang, L.; Chen, L.; Dong, H. Plant aquaporins in infection by and immunity against pathogens- A critical
review. Front. Plant. Sci 2019, 10, 632. https://doi.org/10.3389/fpls.2019.00632.
5. Preston, G.M.; Carroll, T.P.; Guggino, W.B.; Agre, P. Appearance of water channels in Xenopus oocytes
expressing red cell CHIP28 protein. Science 1992, 256, 385-387.
https://doi.org/10.1126/science.256.5055.385
6. Tyerman, S.D.; Niemietz, C.M.; Bramley, H. Plant aquaporins: multifunctional water and solute channels
with expanding roles. Plant cell, and Environment 2002, 25, 173-194. https://doi.org/10.1046/j.0016-
8025.2001.00791.x
7. Verkman, A.S. Aquaporins. Current Biology 2013, 23, PR52-R55. https://doi.org/10.1016/j.cub.2012.11.025
8. King, L.S.; Yasui, M.; Agre, P. Aquaporins in health and disease. Molecular medicine today 2000, 6, P60-
65. https://doi.org/10.1016/s1357-4310(99)01636-6.
9. Boury-Jamot, M.; Sougrat, R.; Tailhardat, M.; Le Varlet, B.; Bonte, F.; Dumas, M.; Verbavatz, J. M.
Expression and function of aquaporins in human skin: Is aquaporin-3 just a glycerol transporter? Biochimica
et Biophysica Acta (BBA) Biomembranes 2006, 1758, 1034-1042.
https://doi.org/10.1016/j.bbamem.2006.06.013.
10. Hara, M.; Ma, T.; Verkman A. S. Selectively reduced glycerol in skin of aquaporin-3 deficient mice may
account for impaired skin hydration, elasticity, and barrier recovery. J. Biol. Chem. 2002, 277, 46616–46621.
https://doi.org/10.1074/jbc.M209003200.
11. Matsuzaki, T.; Tajika, Y.; Ablimit, A.; Aoki, T.; Hagiwara, H.; Takata, K. Aquaporins in the digestive
system. Med. Electron. Microsc 2004, 37, 71–80. https://doi.org/10.1007/s00795-004-0246-3.
12. Ma, T.; Jayaraman, S.; Wang, K.S.; Song, Y.; Yang, B.; Li, J.; Bastidas, J.A.; Verkman, A.S. Defective
dietary fat processing in transgenic mice lacking aquaporin-1 water channels. Am. J. Physiol. Cell Physiol.
2001, 280, C126–C134. https://doi.org/10.1152/ajpcell.2001.280.1.C126.
13. Matsuzaki, T.; Suzuki, T.; Koyama, H.; Tanaka, S.; Takata, K. Water channel protein AQP3 is present in
epithelia exposed to the environment of possible water loss.J. Histochem. Cytochem. 1999, 47, 1275–1286,
https://doi.org/10.1177/002215549904701007.
14. Wang, K.S.; Ma, T.; Filiz, F.; Verkman, A.S.; Bastidas, J.A. Colon water transport in transgenic mice lacking
aquaporin-4 water channels. Am. J. Physiol. Gastrointest. Liver Physiol. 2000, 279, G463–G470,
https://doi.org/10.1152/ajpgi.2000.279.2.G463.
15. Hurley, P.T.; Ferguson, C.J.; Kwon, T.H;, Andersen, M.L.; Norman, A.G.; Steward, M.C.; Nielsen, S.;
Maynard Case, R. Expression and immunolocalization of aquaporin water channels in rat exocrine pancreas.
Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 280, G701–G709.
https://doi.org/10.1152/ajpgi.2001.280.4.G701
16. Nihei, K.; Koyama, Y.,; Tani, T.; Yaoita, E.; Ohshiro, K.; Adhikary, L.P.; Kurosaki, I.; Shirai, Y.;
Hatakeyama, K.; Yamamoto, T. Immunolocalization of aquaporin- 9 in rat hepatocytes and Leydig cells.
Arch. Histol. Cytol. 2001, 64, 81–88.https://doi.org/10.1679/aohc.64.81.
17. McConnell, N.A.; Yunus, R.S.; Gross, S.A.; Bost, K.L.; Clemens, M.G.; Hughes, F.M. Water permeability
of an ovarian antral follicle is predominantly transcellular and mediated by aquaporins. Endocrinology 2002,
143, 2905–2912. https://doi.org/10.1210/endo.143.8.8953.
18. Chen, Q.; Duan, E.K. Aquaporins in sperm osmoadaptation: an emerging role for volume regulation. Acta
Pharmacol. Sin. 2011, 32, 721–724. https://doi.org/org/10.1038/aps.2011.35
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
700
19. Xiong, Z.; Li, B.; Wang, L.; Zeng, X.; Li, B.; Sha, X.; Liu, H. AQP8 and AQP9 expression in patients with
polycystic ovary syndrome and its association with in vitro fertilization-embryo transfer outcomes. Exp Ther
Med. 2019,18, 755–760. https://doi.org/10.3892/etm.2019.7592.
20. Zhang, T.; Lee, Y.W.; Rui, Y.F.; Cheng, T.Y.; Jiang, X.H.; Li, G. Bone marrow-derived mesenchymal stem
cells promote growth and angiogenesis of breast and prostate tumors. Stem Cell Res. Ther. 2013, 4.
https://doi.org/10.1186/scrt221.
21. Yusupov, M.; Razzokov, J.; Cordeiro, R.M.; Bogaerts, A. Transport of reactive oxygen and nitrogen species
across aquaporin: A molecular level picture. Oxid. Med. Cell Longev. 2019, 2930504.
https://doi.org/10.1155/2019/2930504.
22. Cheng, Y.S.; Dai, D.Z.; Dai, Y. AQP4 KO exacerbating renal dysfunction is mediated by endoplasmic
reticulum stress and p66Shc and is attenuated by apocynin and endothelin antagonist CPU0213. European
journal of pharmacology 2013, 721, 249-258. https://doi.org/10.1016/j.ejphar.2013.09.028.
23. Danielson, J.Å.;& Johanson, U. Unexpected complexity of the aquaporin gene family in the moss
Physcomitrella patens.BMC Plant Biology 2008, 8, 45. https://doi.org/10.1186/1471-2229-8-45.
24. Bill, R.; Hedfalk, K.; Karlgren, S.; Mullins, J.; Rydstrom, J.; Hohmann, S. Analysis of the Pore of the Unusual
Major Intrinsic Protein Channel, Yeast Fps1p. J. Biol. Chem.. 2001, 276, 36543–36549.
https://doi.org/10.1074/jbc.M105045200.
25. Scheuring, S.; Ringler, P.; Borgnia, M.; Stahlberg, H.; Muller, D.; Agre, P.;Engel, A. High Resolution AFM
Topographs of the Escherichia coli Water Channel Aquaporin Z. EMBO J. 1999, 18, 4981–4987.
https://doi.org/10.1093/emboj/18.18.4981.
26. Kruse, E.; Uehlein, N.; Kaldenhoff, R. The aquaporins.Genome biology 2006, 7,
206.https://doi.org/10.1186/gb-2006-7-2-206.
27. Eskandari, S.; Wright, E.; Kreman, M.; Starace, D.; Zampighi, G. Structural Analysis of Cloned Plasma
Membrane Proteins by Freeze-Fracture Electron Microscopy. Proc. Natl. Acad. Sci. USA. 1998, 95, 11235–
11240.https://doi.org/10.1073/pnas.95.19.11235.
28. Boassa, D.; Yool, A. A Fascinating Tail: cGMP Activation of Aquaporin-1 Ion Channels, Trends
Pharmacol.Sci.2002, 23, 558–562.https://doi.org/10.1016/S0165-6147(02)02112-0.
29. Nielsen, S.; Agre, P. The aquaporin family of water channels in kidney. Kidney International 1995, 48(4),
1057-1068. https://doi.org/10.1038/ki.1995.389
30. Fu, D.; Libson, A.; Miercke, L.; Weitzman, C.; Nollert, P.; Krucinski, J.; Stroud, R. Structure of a Glycerol-
Conducting Channel and the Basis for Its Selectivity, Science 2000, 290, 481–486.
https://doi.org/10.1126/science.290.5491.481
31. Shapiguzov, A.Y. Aquaporins: structure, systematics, and regulatory features.Russian Journal of Plant
Physiology 2004, 51, 127-137. https://doi.org/10.1023/B:RUPP.0000011313.02617.49.
32. Tajkhorshid, E.; Nollert, P.; Jensen, M.; Miercke, L.; O’Connell, J.; Stroud, R.; Schulten, K. Control of the
Selectivity of the Aquaporin Water Channel Family by Global Orientational Tuning. Science 2002, 296, 525–
530. https://doi.org/10.1126/science.1067778.
33. Wang, F.; Feng, X.C.; Li, Y.M.; Yang, H.; Ma, T.H. Aquaporins as potential drug targets 1. Acta
Pharmacologica Sinica 2006, 27, 395-401. https://doi.org/ 10.1111/j.1745-7254.2006.00318.x
34. Xu, G.Y.;Wang, F.; Jiang, X.; Tao, J. Aquaporin 1, a potential therapeutic target for migraine with
aura.Molecular pain2010, 6, 1744-8069.https://doi.org/10.1186/1744-8069-6-68
35. Gorin, M.B.; Yancey, S.B.; Cline, J.; Revel, J.P.; Horwitz, J. The major intrinsic protein (MIP) of the bovine
lens fiber membrane: characterization and structure based on cDNA cloning. Cell 1984, 39, 49-59.
https://doi.org/10.1016/0092-8674(84)90190-9.
36. Agre, P. Molecular physiology of water transport: aquaporin nomenclature workshop. Mammalian
aquaporins. Biology of the Cell 1997, 89, 255-257. https://doi.org/10.1111/j.1768-322X.1997.tb01021.x.
37. Mulders, S.M.; Preston, G.M.; Deen, P.M.; Guggino, W.B.; van’Os, C.H.; Agre, P. Water channel properties
of major intrinsic protein of lens. Journal of Biological Chemistry 1995, 270, 9010-9016.
https://doi.org/10.1074/jbc.270.15.9010.
38. Berry, V.; Francis, P.; Kaushal, S.; Moore, A.; Bhattacharya, S. Missense mutations in MIP underlie
autosomal dominant ‘polymorphic’and lamellar cataracts linked to 12q. Nature genetics 2000, 25, 15.
https://doi.org/10.1038/75538.
39. Murata, K.; Mitsuoka, K.; Hirai, T.; Walz, T.; Agre, P.; Heymann, J.B.; Engel, A.; Fujiyoshi, Y. Structural
determinants of water permeation through aquaporin-1. Nature 2000, 407, 599–
605.https://doi.org/10.1038/35036519.
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
701
40. Conner, M.T.; Conner, A.C.; Brown, J.E.; Bill, R.M. Membrane trafficking of aquaporin 1 is mediated by
protein kinase C via microtubules and regulated by tonicity. Biochemistry 2010, 49, 821-823.
https://doi.org/10.1021/bi902068b.
41. King, L.S.; Choi, M.; Fernandez, P.C.; Cartron, J.P.; Agre, P. Defective urinary concentrating ability due to
a complete deficiency of aquaporin-1. N Engl J Med 2001, 345, 175-179.
https://doi.org/10.1023/A:1015239915543.
42. Fushimi, K.; Uchida, S.;Harat, Y.; Hirata, Y.; Marumo, F.; Sasaki, S. Cloning and expression of apical
membrane water channel of rat kidney collecting tubule. Nature 1993, 361, 549-552.
https://doi.org/10.1038/361549a0.
43. Nedvetsky, P.I.; Tamma, G.; Beulshausen, S.; Valenti, G.; Rosenthal, W.; Klussmann, E. Regulation of
aquaporin-2 trafficking. Handb Exp Pharmacol 2009, 190,133-57. https://doi.org/10.1007/978-3-540-79885-
9_6.
44. Deen, P.M.; Weghuis, D.O.; Sinke, R.J.; van Kessel, A.G.; Wieringa, B.;Van’Os, C.H. Assignment of the
human gene for the water channel of renal collecting duct aquaporin 2 (AQP2) to chromosome 12 region
q12→ q13.Cytogenetic and Genome Research 1994, 66, 260-262.https://doi.org/10.1159/000133707.
45. Yang, B. The human aquaporin gene family.Current genomics 2000, 1, 91-102.
https://doi.org/10.2174/1389202003351832.
46. Ma, T.; Yang, B.; Kuo, W.L.; Verkman, A.S. cDNA cloning and gene structure of a novel water channel
expressed exclusively in human kidney: evidence for a gene cluster of aquaporins at chromosome locus
12q13. Genomics 1996, 35, 543-550. https://doi.org/10.1006/geno.1996.0396.
47. Osorio, G.; Zulueta-Dorado, T.; González-Rodríguez, P.; Bernabéu-Wittel, J.; Conejo-Mir, J.; Ramírez-
Lorca, R.; Echevarría, M. Expression Pattern of Aquaporin 1 and Aquaporin 3 in Melanocytic and
Nonmelanocytic Skin Tumors. Am. J. Clin. Pathol. 2019, 152, 446–457,https://doi.org/10.1093/ajcp/aqz066.
48. Sougrat, R.; Gobin, R.; Verbavatz, J.M.; Morand, M.; Gondran, C.; Barré, P.; Dumas, M. Functional
expression of AQP3 in human skin epidermis and reconstructed epidermis. Journal of Investigative
Dermatology 2002, 118, 678-685. https://doi.org/10.1046/j.1523-1747.2002.01710.x.
49. Zelenina, M.; Bondar, A.A.; Zelenin, S.; Aperia, A. Nickel and extracellular acidification inhibit the water
permeability of human aquaporin-3 in lung epithelial cells. Journal of Biological Chemistry 2003, 278,
30037-30043. https://doi.org/10.1074/jbc.M302206200.
50. Ma, T.; Fukuda, N.; Song, Y.; Matthay, M.A.; Verkman, A.S. Lung fluid transport in aquaporin-5 knockout
mice, J. Clin. Invest. 2000, 105, 93–100.https://doi.org/10.1172/JCI8258.
51. Hasegawa, H.; Ma, T.; Skach, W.; Matthay, M.A.; Verkman, A. S. Molecular cloning of a mercurial-
insensitive water channel expressed in selected water-transporting tissues.Journal of Biological Chemistry
1994, 269, 5497-5500. https://doi.org/10.1016/S0021-9258(17)37486-0.
52. Jung, J.S.; Bhat, R.V.; Preston, G.M.; Guggino, W.B.; Baraban, J.M.; Agre, P. Molecular characterization of
an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proceedings of the
National Academy of Sciences 1994, 91, 13052-13056.https://doi.org/10.1073/pnas.91.26.13052.
53. Lu, M.; Lee, M.D.; Smith, B.L.; Jung, J.S.; Agre, P.; Verdijk, M.A.; Deen, P. M. The human AQP4 gene:
definition of the locus encoding two water channel polypeptides in brain. Proceedings of the National
Academy of Sciences 1996, 93, 10908-10912, https://doi.org/10.1073/pnas.93.20.10908.
54. Hiroaki, Y.; Tani, K.; Kamegawa, A.; Gyobu, N.; Nishikawa, K.; Suzuki, H.; Mizoguchi, A. Implications of
the aquaporin-4 structure on array formation and cell adhesion.Journal of molecular biology 2006, 355, 628-
639. https://doi.org/10.1016/j.jmb.2005.10.081
55. Ho, J.D.; Yeh, R.; Sandstrom, A.; Chorny, I.; Harries, W.E.; Robbins, R.A.;Stroud, R.M. Crystal structure of
human aquaporin 4 at 1.8Å and its mechanism of conductance.Proceedings of the National Academy of
Sciences. 2009, 106, 7437-7442. https://doi.org/10.1073/pnas.0902725106.
56. Horsefield, R.; Nordén, K.; Fellert, M.; Backmark, A.; Törnroth-Horsefield, S.; van Scheltinga, A.C.; Neutze,
R. High-resolution x-ray structure of human aquaporin 5. Proceedings of the National Academy of Sciences
2008, 105, 13327-13332. https://doi.org/10.1073/pnas.0801466105.
57. Raina, S.; Preston, G.M.; Guggino, W.B.; Agre, P. Molecular cloning and characterization of an aquaporin
cDNA from salivary, lacrimal, and respiratory tissues. Journal of Biological Chemistry 1995, 270, 1908-
1912. https://doi.org/10.1074/jbc.270.4.1908.
58. Kreda, S.M.; Gynn, M.C.; Fenstermacher, D.A.; Boucher, R.C.; Gabriel, S.E. Expression and localization of
epithelial aquaporins in the adult human lung. American journal of respiratory cell and molecular biology
2001, 24, 224-234. https://doi.org/10.1165/ajrcmb.24.3.4367.
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
702
59. Thiagarajah, J.R.; Verkman, A.S. Aquaporin deletion in mice reduces corneal water permeability and delays
restoration of transparency after swelling. Journal of Biological Chemistry 2002, 277, 19139-19144.
https://doi.org/10.1074/jbc.M202071200.
60. Nejsum, L.N.; Kwon, T.H.; Jensen, U.B.; Fumagalli, O.; Frøkiaer, J.; Krane, C.M.; Nielsen, S. Functional
requirement of aquaporin-5 in plasma membranes of sweat glands. Proceedings of the national academy of
sciences 2002, 99, 511-516. https://doi.org/10.1073/pnas.012588099.
61. Song, Y.; Sonawane, N.; Verkman, A. S. Localization of aquaporin‐5 in sweat glands and functional analysis
using knockout mice. The Journal of physiology 2002, 541, 561-568,
https://doi.org/10.1113/jphysiol.2001.020180.
62. Tsubota, K.; Hirai, S.; King, L.S.; Agre, P.; Ishida, N. Defective cellular trafficking of lacrimal gland
aquaporin-5 in Sjögren's syndrome. The Lancet 2001, 357, 688-689. https://doi.org/10.1016/S0140-
6736(00)04140-4.
63. Ma, T.; Verkman, A.S. Aquaporin water channels in gastrointestinal physiology. The Journal of Physiology.
2004, 517, 317-326. https://doi.org/10.1111/j.1469-7793.1999.0317t.x.
64. Moore, M.; Ma, T.; Yang, B.; Verkman, A.S. Tear secretion by lacrimal glands in transgenic mice lacking
water channels AQP1, AQP3, AQP4 and AQP5. Experimental eye research 2000, 70, 557-562.
https://doi.org/10.1006/exer.1999.0814.
65. Yasui, M.; Hazama, A.; Kwon, T.H.; Nielsen, S.; Guggino, W.B.; Agre, P. Rapid gating and anion
permeability of an intracellular aquaporin. Nature 1999, 402, 184-187. https://doi.org/10.1038/46045.
66. Ishibashi, K.; Kuwahara, M.; Gu, Y.; Kageyama, Y.; Tohsaka, A.; Suzuki, F.; Sasaki, S. Cloning and
functional expression of a new water channel abundantly expressed in the testis permeable to water, glycerol,
and urea. Journal of Biological Chemistry 1997, 272, 20782-20786.
https://doi.org/10.1074/jbc.272.33.20782.
67. de Maré, S.W.; Venskutonytë, R.; Eltschkner, S.; de Groot, B.L.;Lindkvist-Petersson, K. Structural basis for
glycerol efflux and selectivity of human aquaporin 7. Structure 2019, 28, 215.e3–222.e3.
https://doi.org/10.1016/j.str.2019.11.011.
68. Moss, F.J.; Mahinthichaichan, P.; Lodowski, D.T.; Kowatz, T.; Tajkhorshid, E.; Engel, A.; Boron, W.F.;
Vahedi-Faridi, A. Aquaporin-7: A Dynamic Aquaglyceroporin with greater water and glycerol permeability
than Its bacterial homolog GlpF. Front. Physiol, 2020, 11, 728, https://doi.org/10.3389/fphys.2020.00728.
69. Rodriguez, R.A.; Chan, R.; Liang, H.; Chen, L.Y. Quantitative study of unsaturated transport of glycerol
through aquaglyceroporin that has high affinity for glycerol. RSC Adv. 2020, 10, 34203-34214.
https://doi.org/10.1039/D0RA05262K
70. Kuriyama, H.; Kawamoto, S.; Ishida, N.; Ohno, I.; Mita, S.; Matsuzawa, Y.; Okubo, K. Molecular cloning
and expression of a novel human aquaporin from adipose tissue with glycerol permeability. Biochemical and
biophysical research communications 1997, 241, 53-58. https://doi.org/10.1006/bbrc.1997.7769.
71. Maeda, N.; Funahashi, T.; Hibuse, T.; Nagasawa, A.; Kishida, K.; Kuriyama, H.; Matsuzawa, Y. Adaptation
to fasting by glycerol transport through aquaporin 7 in adipose tissue. Proceedings of the National Academy
of Sciences 2004, 101, 17801-17806. https://doi.org/10.1073/pnas.0406230101.
72. Skowronski, M.T.; Lebeck, J.; Rojek, A.; Praetorius, J.; Fuchtbauer, E.M.; Frøkiær, J.; Nielsen, S. AQP7 is
localized in capillaries of adipose tissue, cardiac and striated muscle: implications in glycerol metabolism.
American Journal of Physiology-Renal Physiology 2007, 292, F956-F965.
https://doi.org/10.1152/ajprenal.00314.2006.
73. Ma, T.; Yang, B.; Gillespie, A.; Carlson, E.J.; Epstein, C.J.; Verkman, A.S. Generation and phenotype of a
transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4.The Journal of
clinical investigation 1997, 100, 957-962. https://doi.org/10.1172/JCI231.
74. Koyama, Y.; Yamamoto, T.; Kondo, D.; Funaki, H.; Yaoita, E.; Kawasaki, K.; Kihara, I. Molecular cloning
of a new aquaporin from rat pancreas and liver. Journal of Biological Chemistry 1997, 272, 30329-30333.
https://doi.org/10.1074/jbc.272.48.30329.
75. Garcıa, F.; Kierbel, A.; Larocca, M.C.; Gradilone, S.A.; Splinter, P.; LaRusso, N.F.; Marinelli, R.A. The
water channel aquaporin-8 is mainly intracellular in rat hepatocytes, and its plasma membrane insertion is
stimulated by cyclic AMP. Journal of Biological Chemistry 2001, 276, 12147-12152.
https://doi.org/10.1074/jbc.M009403200
76. Ishibashi, K.; Kuwahara, M.; Gu, Y.; Tanaka, Y.; Marumo, F.; Sasaki, S. Cloning and functional expression
of a new aquaporin (AQP9) abundantly expressed in the peripheral leukocytes permeable to water and urea,
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
703
but not to glycerol. Biochemical and biophysical research communications 1998, 244, 268-274.
https://doi.org/10.1006/bbrc.1998.8252.
77. Maeda, N.; Hibuse, T.; Funahashi, T. Role of aquaporin-7 and aquaporin-9 in glycerol metabolism;
involvement in obesity. Aquaporins 2009, 233-249. https://doi.org/10.1007/978-3-540-79885-9_12.
78. Badaut, J.; Petit, J.M.; Brunet, J.F.; Magistretti, P.J.; Charriaut-Marlangue, C.; Regli, L. Distribution of
Aquaporin 9 in the adult rat brain: preferential expression in catecholaminergic neurons and in glial
cells.Neuroscience 2004, 128, 27-38. https://doi.org/10.1016/j.neuroscience.2004.05.042.
79. Rodriguez, A.; Catalan, V.; Gomez-Ambrosi, J.; Garcia-Navarro, S.; Rotellar, F.; Valenti, V.; Silva, C.; Gil,
M.J.; Salvador, J.; Burrell, M.A.; Calamita, G.; Malagon, M.M.; Fruhbeck, G. Insulin- and leptin-mediated
control of aquaglyceroporins in human adipocytes and hepatocytes is mediated via the PI3K/Akt/mTOR
signaling cascade. J. Clin. Endocrinol. Metab. 2011, 96, E586–E597. https://doi.org/10.1210/jc.2010-1408
80. Morishita, Y.; Matsuzaki, T.; Hara-Chikuma, M.; Andoo, A.; Shimono, M.; Matsuki, A.; Kusano, E.
Disruption of aquaporin-11 produces polycystic kidneys following vacuolization of the proximal tubule.
Molecular and cellular biology 2005, 25, 7770-7779. https://doi.org/10.1128/MCB.25.17.7770-7779.2005.
81. Itoh, T.: Rai, T.; Kuwahara, M.; Ko, S.B.; Uchida, S.; Sasaki, S.; Ishibashi, K. Identification of a novel
aquaporin, AQP12, expressed in pancreatic acinar cells. Biochemical and biophysical research
communications 2005, 330, 832-838. https://doi.org/10.1016/j.bbrc.2005.03.046.
82. De Groot, B.; Engel, A.; Grubmuller, H. The Structure of the Aquaporin-1 Water Channel: A Comparison
between Cryo-Electron Microscopy and X-Ray Crystallography, J. Mol. Biol. 2003, 325, 485–493.
https://doi.org/10.1016/s0022-2836(02)01233-0.
83. Yang, B.; Verkman, A.S. Water and glycerol permeabilities of Aquaporins 1-5 and MIP determined
quantitatively by expression of epitope-tagged constructs in Xenopus oocytes. J Biol Chem. 1997, 272, 16140-
16146. https://doi.org/10.1074/jbc.272.26.16140.
84. Chaumont, F.; Barrieu, F.; Jung, R.; Chrispeels, M.J. Plasma membrane intrinsic proteins from maize cluster
in two sequence subgroups with differential aquaporin activity. Plant Physiol. 2000, 122, 1025-1034.
https://doi.org/10.1104/pp.122.4.1025.
85. Fetter, K.; Van Wilder, V.; Moshelion, M.; Chaumont, F. Interactions between plasma membrane aquaporins
modulate their water channel activity. Plant Cell. 2004, 16, 215-228. https://doi.org/10.1105/tpc.017194.
86. Martre, P.; Morillon, R.; Barrieu, F.; North, G.B.; Nobel, P.S.; Chrispeels, M.J. Plasma membrane aquaporins
play a significant role during recovery from water deficit. Plant Physiol. 2002, 130, 2101-2110.
https://doi.org/10.1104/pp.009019.
87. Zardoya, R. Phylogeny and evolution of the major intrinsic protein family. Biol Cell. 2005, 97, 397-414.
https://doi.org/10.1042/BC20040134.
88. Hoffert, J.D.; Leitch, V.; Agre P.; King, L.S. Hypertonic induction of aquaporin-5 expression through an
ERK-dependent pathway, J. Biol. Chem. 2000, 275, 9070–9077. https://doi.org/10.1074/jbc.275.12.9070.
89. Li, C.; Wang, W. Molecular biology of aquaporins. Aquaporins 2017, 969, 1-34. https://doi.org/10.1007/978-
94-024-1057-0_1.
90. Verkman, A.S.; Matthay, M.A.; Song, Y. Aquaporin water channels and lung physiology, Am. J. Physiol.
Lung Cell. Mol. Physiol. 2000, 278, L867–L879. https://doi.org/10.1152/ajplung.2000.278.5.L867.
91. Patil, R.V.; Saito, I.; Yang, X.U.N.; Wax, M.B. Expression of aquaporins in the rat ocular tissue.Experimental
eye research1997, 64, 203-209. https://doi.org/10.1006/exer.1996.0196.
92. Terris, J.; Ecelbarger, C.A.; Nielsen, S.; Knepper, M.A. Long-term regulation of four renal aquaporins in rats.
Am J Physiol.1996, 271, F414–F422. https://doi.org/10.1152/ajprenal.1996.271.2.F414.
93. Wall, S.M.; Han, J.S.; Chou, C.L.; Knepper, M.A. Kinetics of urea and water permeability activation by
vasopressin in rat terminal IMCD. Am J Physiol 1992, 262, F989–F998.
https://doi.org/10.1152/ajprenal.1992.262.6.F989.
94. Nielsen, S.; DiGiovanni, S.R.; Christensen, E.I.; Knepper, M.A.; Harris, H.W. Cellular and subcellular
immunolocalization of vasopressin- regulated water channel in rat kidney. Proc Natl Acad SciUSA. 1993, 90,
11663–11667. https://doi.org/10.1073/pnas.90.24.11663.
95. Tamma, G.; Robben, J.H.; Trimpert, C.; Boone, M.; Deen, P.M. Regulation of AQP2 localization by S256
and S261 phosphorylation and ubiquitination. Am J Physiol Cell Physiol. 2011, 300, C636–
C646.https://doi.org/10.1152/ajpcell.00433.2009.
96. Bui, T.T.; Giovanoulis, G.; Cousins, A.P.; Magnér, J.; Cousins, I.T.; de Wit, C.A. Human exposure, hazard
and risk of alternative plasticizers to phthalate esters. Sci Total Environ 2016, 541, 451-467.
https://doi.org/10.1016/j.scitotenv.2015.09.036.
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
704
97. Guo, L.; Chen, H.; Li, Y.; Zhou, Q.; Sui, Y. An aquaporin 3-notch1 axis in keratinocyte differentiation and
inflammation. PLoS One 2013, 8, e80179. https://doi.org/10.1371/journal.pone.0080179.
98. Yang, F.; Kawedia, J.D.; Menon, A.G. Cyclic AMP regulates aquaporin 5 expressions at both transcriptional
and post-transcriptional levels through a protein kinase A pathway, J. Biol. Chem. 2003, 278, 32173–32180.
https://doi.org/10.1074/jbc.M305149200.
99. Amiry-Moghaddam, M.; Frydenlund, D.S.; Ottersen, O.P. Anchoring of aquaporin-4 in brain: molecular
mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience 2004,
129, 997-1008. https://doi.org/10.1016/j.neuroscience.2004.08.049.
100. Huang, H.F.; He, R.H.; Sun, C.C.; Zhang, Y.; Meng, Q.X.; Ma, Y.Y. Function of aquaporins in female and
male reproductive systems. Hum. Reprod Update 2006, 12, 785–795.
https://doi.org/10.1093/humupd/dml035.
101. Day, R.E.; Kitchen, P.; Owen, D.S.; Bland, C.; Marshall, L.; Conner, A.C.; Conner, M. T. Human aquaporins:
regulators of transcellular water flow. Biochimica et Biophysica Acta (BBA)-General Subjects 2014, 1840,
1492-1506. https://doi.org/10.1016/j.bbagen.2013.09.033.
102. Liu, X.; Bandyopadhyay, B.C.; Nakamoto, T.; Singh, B.; Liedtke, W.; Melvin, J.E.; Ambudkar, I. A role for
AQP5 in activation of TRPV4 by hypotonicity: concerted involvement of AQP5 and TRPV4 in regulation of
cell volume recovery, J. Biol. Chem.2006, 281, 15485–15495. https://doi.org/10.1074/jbc.M600549200.
103. Varadaraj, K.; Kumari, S. Deletion of seventeen amino acids at the C-terminal end of Aquaporin 0 causes
distortion aberration and cataract in the lenses of AQP0DC/DC mice, Invest. Ophthalmol. Vis. Sci. 2019, 60,
858-867. https://doi.org/10.1167/iovs.18-26378.
104. Varadaraj, K.; Gao, J.; Mathias,R.T; Kumari, S. C-terminal end of Aquaporin 0 regulates lens gap junction
channel function, Invest. Ophthalmol. Vis. Sci. 2019, 60, 2525-2531. https://doi.org/10.1167/iovs.19-26787.
105. Kumari, S.S.; Varadaraj, K. A predominant form of C-terminally end-cleaved AQP0 functions as an open
water channel and an adhesion protein in AQP0DC/DC mouse lens, Biochem. Biophys. Res. Commun. 2019,
511, 626-630. https://doi.org/10.1016/j.bbrc.2019.02.098.
106. Gu, S.; Biswas, S.; Rodriguez, L. Connexin 50 and AQP0 are essential in maintaining organization and
integrity of lens fibers. Invest. Ophthalmol. Vis. Sci. 2019, 60, 4021-4032. https:.//doi.org/10.1167/iovs.18-
26270.
107. Saadoun, S.; Bell B.A.; Verkman A.S.; Papadopoulos M.C. Greatly improved neurological outcome after
spinal cord compression injury in AQP4-deficient mice. Brain. 2008, 131, 1087–1098.
https://doi.org/10.1093/brain/awn014.
108. Verkman, A.S.; Mitra, A.K.. Structure and function of aquaporin water channels.American Journal of
Physiology-Renal Physiology 2000, 278, F13-F28. https://doi.org/10.1152/ajprenal.2000.278.1.F13.
109. Kwon, T.H.; Frøkiær, J.; Nielsen, S. Regulation of aquaporin-2 in the kidney: a molecular mechanism of
body-water homeostasis. Kidney research and clinical practice 2013, 32, 96-102.
https://doi.org/10.1016/j.krcp.2013.07.005.
110. Tornroth-Horsefield, S.; Wang, Y.; Hedfalk, K.; Johanson, U.; Karlsson, M.; Tajkhorshid, E.; Neutze, R.;
Kjellbom, P. Structural mechansm of plant aquaporin gating. Nature 2006, 439, 688–
694.https://doi.org/10.1038/nature04316.
111. Rodrigues, C.; Pimpão, C.; Mósca, A.F.; Coxixo, A.S.; Lopes, D.; Da Silva, I.V.; Pedersen, P.A.; Antunes,
F.; Soveral, G. Human Aquaporin-5 Facilitates Hydrogen Peroxide Permeation A_ecting Adaption to
Oxidative Stress and Cancer Cell Migration. Cancers 2019, 11,
932.https://doi.org/10.3390/cancers11070932.
112. Lyublinskaya O.; Antunes F. Measuring intracellular concentration of hydrogen peroxide with the use of
genetically encoded H2O2 biosensor HyPer. Redox Biol. 2019, 24, 101200.
https://doi.org/10.1016/j.redox.2019.101200.
113. Verkman, A.S. Aquaporin water channels and endothelial cell function. Journal of Anatomy 2002, 200, 617-
627. https://doi.org/10.1046/j.1469-7580.2002.00058.x
114. Nagelhus, E.A.; Ottersen, O.P. Physiological Roles of Aquaporin-4 in Brain. Physiological Review. 2013, 93,
1543-1562. https://doi.org/10.1152/physrev.00011.2013.
115. Blaydon, D.; Lind, L.; Plagnol, V.; Linton, K.; Smith, F.D.; Wilson, N.; McLean, W.H.; Munro, C.; South,
A.; Leigh, I.; O'Toole, E.; Lundström, A.; Kelsell, D. Mutations in AQP5, encoding a water-channel protein,
cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma. Am. J. Hum. Genet. 2013,
93, 330–335. https://doi.org/10.1016/j.ajhg.2013.06.008.
116. Prata C.; Hrelia S.; Fiorentini D. Peroxiporins in Cancer.Int. J. Mol. Sci.2019; 20,
1371.https://doi.org/10.3390/ijms20061371.
https://doi.org/10.33263/BRIAC121.690705
https://biointerfaceresearch.com/
705
117. Gresz, V.; Kwon, T.H.; Hurley, P.T.; Varga, G.; Zelles, T.; Nielsen, S.; Case, R.M.; Steward, M.C.
Identification and localization of aquaporin water channels in human salivary glands. Am. J. Physiol.
Gastrointest. Liver Physiol. 2001, 281, G247–G254. https://doi.org/10.1152/ajpgi.2001.281.1.G247.
118. Haj-Yasein, N.N.; Vindedal, G.F.; Eilert-Olsen, M.; Gundersen, G.A.; Skare, O.; Laake, P.; Klungland, A.;
Thoren, A.E.; Burkhardt, J.M.; Ottersen, O.P.; Nagelhus, E.A. Glial-conditional deletion of aquaporin-4
(Aqp4) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet.
Proc. Natl. Acad. Sci. USA. 2011, 108,17815–17820. https://doi.org/10.1073/pnas.1110655108.
119. Sidhaye, V.K.; Guler, A.D.; Schweitzer, K.S.; D'Alessio, F.; Caterina, M.J.; King, L.S. Transient receptor
potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions. Proc. Natl. Acad. Sci. U
SA. 2006, 103, 4747–4752. https://doi.org/10.1073/pnas.0511211103.
