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Aquaporins in Astrocytes: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Jiangshan Zhan.

Astrocytes have distinctive morphological and functional characteristics, and are found throughout the central nervous system. Astrocytes are now known to be far more than just housekeeping cells in the brain. Their functions include contributing to the formation of the blood–brain barrier, physically and metabolically supporting and communicating with neurons, regulating the formation and functions of synapses, and maintaining water homeostasis and the microenvironment in the brain. Aquaporins (AQPs) are transmembrane proteins responsible for fast water movement across cell membranes. Various subtypes of AQPs (AQP1, AQP3, AQP4, AQP5, AQP8 and AQP9) have been reported to be expressed in astrocytes, and the expressions and subcellular localizations of AQPs in astrocytes are highly correlated with both their physiological and pathophysiological functions.

  • aquaporins
  • astrocytes
  • AQP1
  • AQP4
  • water homeostasis

1. Introduction

Aquaporins (AQPs) are transmembrane protein channels. Several subtypes are highly expressed in astrocytes and their selective pores play a crucial role in water and ion homeostasis in the brain [30,31][1][2]. AQPs mediate bidirectional water flux driven by osmotic gradient across cell membranes [2[3][4][5],32,33], and thereby modulate water content in the CSF and blood [34,35][6][7]. Besides maintaining water balance and buffering extracellular ion concentrations, these AQPs have versatile functions in astrocytes. The expression of AQPs significantly affects cell volume regulation [36,37,38][8][9][10]. AQPs are also required in various activities including signal transduction, neuronal excitation [39][11], neurotransmission, synaptic plasticity, learning and memory [40][12], neurogenesis [41[13][14],42], cell adhesion and migration [43,44][15][16] and brain energy metabolism [45][17]. There is still a paucity of studies for a systematic and up-to-date review of AQPs in astrocytes especially their dynamic expression and subcellular localization under physiological and pathological conditions. 

2. Expressions, Subcellular Localizations and Functions of AQP Subtypes in Astrocytes

2.1. AQP1

The first discovery of the existence of a water channel protein, later called aquaporin 1 (AQP1), was made from human erythrocyte cell membrane by Benga’s group in 1985 in Cluj-Napoca, Romania, and published in 1986 [69,134][18][19]. Later, Peter Agre purified the protein of AQP1 for which he won the 2003 Nobel Prize in Chemistry [135][20]. AQP1 has been shown to mediate the transmembrane movement of water in several different organs, including the kidney, eye and brain [53,81,136,137][21][22][23][24]. AQP1 expression in the human brain was first observed under pathological conditions after subarachnoid hemorrhage, and in peritumoral tissue, with the protein being located mainly on the processes of reactive astrocytes [138][25]. AQP1 expression in the uninjured brains was absent or too low to be observed [138,139][25][26]. Nevertheless, the labs of both Ben Barres and Baljit Khakh later confirmed using transcriptome studies that mRNA of AQP1 was indeed expressed by astrocytes [140,141,142][27][28][29]. AQP1 transcripts and protein in cultured astrocytes were also identified, indicating localization of AQP1 on plasma membrane, in the cytoplasm compartment membrane and possibly also on the nuclear membrane [53,133][21][30]. Another interesting finding of AQP1 in culture is that the protein was selectively lost when passaging primary astrocytes, but its mRNA was always detectable [139][26]. The expression of AQP1 in the non-human primate brain was also found to be in the processes and perivascular end-feet of a subtype of astrocytes localized mainly in the white matter and at sites of the glia limitans [48][31]. So far, no isoforms of AQP1 have been reported.
Unlike other AQP subtypes, it has been suggested that AQP1 might harbor the capability of transporting cations after stimulation with adenylate cyclase activator forskolin or protein kinase A in Xenopus egg [72][32]. Further discoveries by the same group indicated that AQP1 is a cGMP-gated cation channel [143,144][33][34] and that it functions as both a water channel and a gated ion-channel in the choroid plexus, contributing to the regulation of CSF production [145][35]. Yool believed that the putative central pore in AQP1 is related to its cation transport functions [1,81,146][22][36][37]. However, other studies reported that such cation transport could not be repeated in similar Xenopus egg models [147,148,149,150,151,152][38][39][40][41][42][43]. In the molecular model presented by Murata and colleagues, the pore was only slightly larger than a typical water molecule, and the formation of hydrogen bonds between water and pore residues allowed only water molecules to pass through the channel [153][44]. Similarly, the determination of the AQP1 crystal structure enabled the elucidation of the mechanism by which water molecules moved through the protein, but the passage of protons and other ions was blocked [30][1]. The mechanisms for cation transport in different tissues and cell types thus still need further clarification. Nevertheless, a recent paper clearly showed that AQP1 can mediate fast swelling kinetics and play a key role in triggering and accelerating regulatory volume decrease, a process where cells adjust their cellular volume in response to swelling [154][45].
AQP1 was also one of the first AQP subtypes reported to facilitate the migration of endothelial cells [155][46] and to promote reactive astrocyte migration [139][26]. Cell migration is a fundamental process in multicellular organisms where tissue formation requires orchestrated movement of cells to specific locations. The migration of astrocytes is important under both, normal and pathological conditions, and the current knowledge of the mechanisms involved was summarized in ourthe recent reviews [43,156][15][47].

2.2. AQP3

AQP3 was first identified in kidney medulla and colon in 1994 [85][48]. It was found to be enriched in kidney collecting ducts and localized on the basolateral cell membrane of their principal cells playing a role in water transport [85,157][48][49]. The existence and physiological function of AQP3 in astrocytes remains debated due to its relatively low abundance in the brain. In 2001, Yamamoto and colleagues showed that AQP3 is expressed in the brain and astrocytes at the mRNA level using reverse transcription–polymerase chain reaction [51][50]. At the protein level, Yang et al. reported the induction of AQP3 expression in primary astrocyte cultures with hyperosmotic exposure using Western blot [158][51]. Moreover, AQP3 is induced and co-localized with GFAP-positive astrocytes after permanent focal cerebral ischemia [87][52]. It is worth mentioning that recent studies indicate there might be a continuum existing between GFAP-expressing astrocytes and other cell types such as oligodendrocytes [159][53]. It warrants further studies to better elucidate the role of AQP3 in astrocytes.

2.3. AQP4

2.3.1. Isoforms of AQP4

AQP4 was identified by Peter Agre in 1994 [88][54] and is currently the most studied AQP in relation to its properties in astrocytes. The expression level of AQP4 in astrocytes is the highest among all AQP subtypes [137,140,141,142][24][27][28][29]. So far, eight isoforms of AQP4 have been reported. These include AQP4a (M1), AQP4b, AQP4c (M23), AQP4d, AQP4e (AQP4 Mz), AQP4f, AQP4-△4 and AQP4ex [160,161,162,163][55][56][57][58]. Most reports on AQP4 subcellular localizations and functions refer to the two major isoforms AQP4a (M1) and AQP4c (M23), which were the earliest found to be expressed and localized in the plasma membrane, particularly at the end-feet of rat astrocytes, and have water permeabilities [164,165,166][59][60][61]. AQP4c is known to form higher-order structures called orthogonal arrays of particles (OAPs) in the plasma membrane, which are distinctive square arrays of particles originally seen and most densely concentrated in the plasma membrane of astrocytes [167,168,169][62][63][64]. AQP4a can co-assemble with AQP4c to form these OAPs albeit of smaller size [44,170,171][16][65][66]. Although there are as yet no reports regarding the protein of AQP4a and AQP4c in human astrocytes, studies of the human AQP4 genes in the brain did indicate two distinct mRNAs corresponding to these two functionally active isoforms found in the rat [172][67]. AQP4b, AQP4d, AQP4e and AQP4f were identified in the rat brain in 2008 [160][55]. Of these four AQP4 isoforms, AQP4b and AQP4d are localized extensively in acidic compartments such as endosomes or lysosomes, and the Golgi apparatus, but they do not contribute to OAPs in the plasma membrane in transfected rat astrocytes [173][68]. AQP4e was confirmed to have water permeability and is predominantly localized in the plasma membrane, with a minor amount in Golgi apparatus and degradation compartments [130,160][55][69]. Similar to AQP4a, AQP4e is unable to form OAPs by itself but can associate with AQP4c to form OAPs [161,170][56][65]. Moreover, AQP4e was found to have a novel effect on OAP reorganization and participated in the regulation of astrocyte cell volume [174][70]. However, due to the presence of in-frame stop codons, AQP4e was only found in rat brains and not in humans or mice [161][56]. AQP4f was believed to partially localize to the Golgi apparatus [160][55]. The water transport capacity of the isoforms AQP4b, AQP4d and AQP4f are not clear yet [137][24], and no information on these three isoforms in humans is available to date.
AQP4-△4 lacks exon 4 and is found in human skeletal muscle. There is no information on whether it is inherently expressed in astrocytes or not. AQP4-△4 transfected in HeLa cells resides mainly in the endoplasmic reticulum and does not show any water transport capacity [162][57]. Moreover, AQP4-△4 transfected into astrocytes with stable expression of functional AQP4 could reduce the expression level of full-length AQP4 in the cell membrane [162][57]. These findings suggest that AQP4-△4 may act as a pre-form of AQP4 in regulating water transport across cell membranes.
On the other hand, AQP4ex is characterized by a C-terminal extension that is generated by a programmed translational read-through and was recently identified in human, rat and mouse astrocytes [163,175,176][58][71][72]. AQP4ex appears to be similar to AQP4a and AQP4c in terms of being present in OAPs, required to address OAPs to the perivascular astrocyte end-feet, and able to modulate OAP size and water transport [163,175,176][58][71][72].
Since all these isoforms originated from the same pre-mRNA transcript after alternative splicing, each AQP4 isoform might play a role in influencing the total composition of AQP4 in a cell. However, it is unclear whether the proposed interactions among AQP4 isoforms would ultimately contribute to the exquisite water homeostasis function in astrocytes under both normal and pathological conditions.

2.3.2. AQP4 Polarization

AQP4 polarization occurs in astrocytes, referring to its ‘polarized’ expression primarily in the perivascular astrocytic end-feet domains (Figure 1). Polarization is highly responsive to the extracellular microenvironment and has a preference for areas in contact with the fluid compartments in or around the central nervous system (CNS). This is best demonstrated in the specific occurrence of polarization in the boundary between parenchyma and major fluid compartments such as the brain–blood interface, the brain–subarachnoid CSF interface (glia limitans), and the brain–ventricular CSF interface (sub-ependymal astrocytes) [177,178][73][74]. AQP4 is diffusely expressed in astrocyte end-feet covering blood vessels throughout the hippocampus [179][75]. In the cerebral cortex, AQP4 is more enriched in the end-feet membranes adjacent to capillaries than in the parenchymal membranes and the degree of astrocytic polarization is species-dependent [178,180,181][74][76][77]. In general, the predominant subcellular localization of AQP4 is in the astrocyte end-feet membranes directly in contact with the brain capillaries and the pia mater, and with a low but significant concentration in non-end-feet membranes, such as those astrocyte membranes that ensheath glutamatergic synapses [10,178][74][78]. In the spinal cord, similar to the situation in the brain, AQP4 is primarily expressed in the astrocyte end-feet surrounding blood vessels. However, a strong AQP4 signal could also be found in astrocyte process wrapped around myelinated nerve fibers [46][79]. AQP4 polarization is not found in cultured cells, where AQP4 was found to be evenly distributed throughout the cell membrane under normal conditions [130[69][80],182], even though these in vitro water channels were functional [183][81].

2.4. AQP5

AQP5 was first identified in rat salivary glands in 1995 [96][82] and has been shown to convey a high degree of membrane water permeability in corneal, pancreatic, and bronchial epithelium, the secretory cells in salivary and lacrimal glands, airway submucosal glands and type I pneumocytes of the respiratory tract [36,231,232][8][83][84].
AQP5 was first identified in primary cultures of rat astrocytes at the mRNA level, and its protein was observed in reactive astrocytes surrounding the lesion site of the hippocampus after middle cerebral artery occlusion (MCAO) induction in rats [51][50]. As expected, only low-level expression of AQP5 was observed in human normal brain tissue [233][85]. AQP5 protein was also detected in the piriform cortex, choroid plexus, dorsal thalamus and cerebellum Bergmann glia cells in rat brain [52][86]. The expression of AQP5 in primary cultures of mouse cerebral cortical astrocytes at both mRNA and protein levels was further identified by ourthe group [53][21]. By using RNA-sequencing, Ben Barres’ group confirmed AQP5 expression in human astrocytes [141][28]. No isoforms of AQP5 have as yet been identified.
AQP5 localizes in both the plasma membrane and the cytoplasmic compartment membranes in primary astrocyte cultures [53][21]. The AQP5 expression was very low in 1-week primary astrocyte cultures but increased dramatically after 2 weeks [53,127,128][21][87][88]. Similar to AQP1 and AQP4, AQP5 is also permeable to water [7[89][90],234], and able to activate ion channel protein TPRV4 and take part in regulatory volume decrease [37][9]. Therefore, AQP5 in astrocytes may participate in water transportation and astrocytic regulatory volume decrease, regulating the osmotic pressure needed for neuronal functions in the brain. In addition, AQP5 can facilitate astrocyte migration. In the primary culture model wresearche rs built, AQP5 increased and polarized to the migrating processes and the leading edge cytoplasmic membrane of astrocytes, and its over-expression facilitated astrocyte process elongation [53][21].

2.5. AQP8

AQP8 was initially described to be highly expressed in the testis and the liver [235][91] and was later reported also to be expressed in neural tissues (Table 2). Both AQP8 mRNA and protein expression have been determined in primary cultures of rat astrocytes [51,158][50][51]. The protein expression of AQP8 was observed in astrocytes in the mouse spinal cord in 2004 [103][92]. Later, AQP8 expression was also demonstrated in astrocytes in the rat brain [52,87][52][86]. Interestingly, considerable AQP8 mRNA was detected in adult NSCs, and its predominant expression was found in the mitochondria-enriched fraction indicating a possible role of AQP8 in regulating mitochondrial volume during NSC differentiation [59][93]. So far, three isoforms of AQP8 have been found: the full-length AQP8 transcript and two other splice isoforms discovered in pig testis [236][94]. Further investigations on AQP8 are required to clarify its expression and physiological roles in astrocytes and the NSCs.

2.6. AQP9

AQP9 was first identified in peripheral leukocytes in 1998 [116][95]. AQP9 is an aquaglyceroporin and functions in the transport of water, urea and glycerol [116,117,237,238][95][96][97][98]. It was later found to also transport mannitol, purines and pyrimidines (Table 2) [137,177,222,239,240,241,242] [24][73][99][100][101][102][103].
AQP9 expression in astrocytes was also confirmed in transcriptome studies, and its expression was higher in rodent brains than in human brains [140,141,142][27][28][29]. AQP9 protein was detected in glia limitans, white matter and gray matter of the rodent and non-human primate brain [60,61][104][105] To date, two isoforms of AQP9 have been identified in the brain [239][100]: the long isoform, which appears to correspond to the liver isoform, is expressed throughout the astrocyte plasma membrane, whereas the short isoform is expressed in the mitochondria with higher enrichment in the inner mitochondrial membrane [60,239][100][104] and a potential role in transporting lactic acid into the mitochondria [239,243][100][106]. AQP9 is therefore very likely to be involved in brain metabolism.
In addition to AQP4 and AQP8, AQP9 was a key protein examined in NSC studies. AQP9 is expressed in adult murine subventricular zone- (SVZ-) derived NSCs [41][13] but it has as yet not been found in human NSCs [41,42][13][14]. It was reported that the levels of expression and cellular localization of AQP4 and AQP9 were differentially regulated upon differentiation of SVZ-derived NSCs into glial cells and neurons, indicating that AQP4 and AQP9 likely play different roles in these cells [41][13].
Although AQP9 expression and subcellular localization have been identified in NSCs and astrocytes, interpretation of these data should be undertaken with caution. The inconsistencies between various studies may sometimes be due to the cross-reactivity with nonspecific epitopes for some AQP9 antibodies [62,244][107][108]. Using AQP9 knockout mice, Rojek and colleagues demonstrated that AQP9 expression discovered in the mice brain could be due to artifacts related to the specificity of the anti-AQP9 antibodies used [238][98]. However, Mylonakou et al. showed that AQP9 mRNA was present in the cells where the same AQP9 immunoreactivity was observed through in situ hybridization [62][107]. In the same study, a lower level of AQP9 mRNA was found in mouse brain than in rat brain, which may well explain such discrepancy. Nevertheless, heterogeneity of AQP9 expression in different species and its existence of different splice variants need also to be considered. The development of novel tools with higher specificity would help to confirm the results of AQP9 expression and unravel the roles of AQP9 in astrocytes and CNS.

References

  1. Zeuthen, T. How water molecules pass through aquaporins. Trends Biochem. Sci. 2001, 26, 77–79.
  2. Day, R.E.; Kitchen, P.; Owen, D.S.; Bland, C.; Marshall, L.; Conner, A.C.; Bill, R.M.; Conner, M.T. Human aquaporins: Regulators of transcellular water flow. Biochim. Biophys. Acta 2014, 1840, 1492–1506.
  3. Amiry-Moghaddam, M.; Ottersen, O.P. The molecular basis of water transport in the brain. Nat. Rev. Neurosci. 2003, 4, 991–1001.
  4. Praetorius, J. Water and solute secretion by the choroid plexus. Pflug. Arch. 2007, 454, 1–18.
  5. Yang, B. Aquaporins; Springer: Dordrecht, The Netherlands, 2017.
  6. 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.; et al. 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.
  7. Iliff, J.J.; Wang, M.; Liao, Y.; Plogg, B.A.; Peng, W.; Gundersen, G.A.; Benveniste, H.; Vates, G.E.; Deane, R.; Goldman, S.A.; et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 2012, 4, 147ra111.
  8. Krane, C.M.; Melvin, J.E.; Nguyen, H.V.; Richardson, L.; Towne, J.E.; Doetschman, T.; Menon, A.G. Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation. J. Biol. Chem. 2001, 276, 23413–23420.
  9. 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.
  10. Benfenati, V.; Caprini, M.; Dovizio, M.; Mylonakou, M.N.; Ferroni, S.; Ottersen, O.P.; Amiry-Moghaddam, M. An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes. Proc. Natl. Acad. Sci. USA 2011, 108, 2563–2568.
  11. Binder, D.K.; Yao, X.; Zador, Z.; Sick, T.J.; Verkman, A.S.; Manley, G.T. Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 2006, 53, 631–636.
  12. Szu, J.I.; Binder, D.K. The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory. Front. Integr. Neurosci. 2016, 10, 8.
  13. Cavazzin, C.; Ferrari, D.; Facchetti, F.; Russignan, A.; Vescovi, A.L.; La Porta, C.A.; Gritti, A. Unique expression and localization of aquaporin-4 and aquaporin-9 in murine and human neural stem cells and in their glial progeny. Glia 2006, 53, 167–181.
  14. Kong, H.; Fan, Y.; Xie, J.; Ding, J.; Sha, L.; Shi, X.; Sun, X.; Hu, G. AQP4 knockout impairs proliferation, migration and neuronal differentiation of adult neural stem cells. J. Cell Sci. 2008, 121, 4029–4036.
  15. Zhan, J.S.; Gao, K.; Chai, R.C.; Jia, X.H.; Luo, D.P.; Ge, G.; Jiang, Y.W.; Fung, Y.W.; Li, L.; Yu, A.C. Astrocytes in Migration. Neurochem. Res. 2017, 42, 272–282.
  16. Hiroaki, Y.; Tani, K.; Kamegawa, A.; Gyobu, N.; Nishikawa, K.; Suzuki, H.; Walz, T.; Sasaki, S.; Mitsuoka, K.; Kimura, K.; et al. Implications of the aquaporin-4 structure on array formation and cell adhesion. J. Mol. Biol. 2006, 355, 628–639.
  17. Badaut, J.; Regli, L. Distribution and possible roles of aquaporin 9 in the brain. Neuroscience 2004, 129, 971–981.
  18. Benga, G.; Popescu, O.; Borza, V.; Pop, V.I.; Muresan, A.; Mocsy, I.; Brain, A.; Wrigglesworth, J.M. Water permeability in human erythrocytes: Identification of membrane proteins involved in water transport. Eur. J. Cell Biol. 1986, 41, 252–262.
  19. Benga, G.; Popescu, O.; Pop, V.I.; Holmes, R.P. p-(Chloromercuri)benzenesulfonate binding by membrane proteins and the inhibition of water transport in human erythrocytes. Biochemistry 1986, 25, 1535–1538.
  20. Denker, B.M.; Smith, B.L.; Kuhajda, F.P.; Agre, P. Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules. J. Biol. Chem. 1988, 263, 15634–15642.
  21. Chai, R.C.; Jiang, J.H.; Wong, A.Y.; Jiang, F.; Gao, K.; Vatcher, G.; Hoi Yu, A.C. AQP5 is differentially regulated in astrocytes during metabolic and traumatic injuries. Glia 2013, 61, 1748–1765.
  22. Yool, A.J. Aquaporins: Multiple roles in the central nervous system. Neuroscientist 2007, 13, 470–485.
  23. Kitchen, P.; Day, R.E.; Salman, M.M.; Conner, M.T.; Bill, R.M.; Conner, A.C. Beyond water homeostasis: Diverse functional roles of mammalian aquaporins. Biochim. Biophys. Acta 2015, 1850, 2410–2421.
  24. Potokar, M.; Jorgacevski, J.; Zorec, R. Astrocyte Aquaporin Dynamics in Health and Disease. Int. J. Mol. Sci. 2016, 17, 1121.
  25. Badaut, J.; Brunet, J.F.; Grollimund, L.; Hamou, M.F.; Magistretti, P.J.; Villemure, J.G.; Regli, L. Aquaporin 1 and aquaporin 4 expression in human brain after subarachnoid hemorrhage and in peritumoral tissue. Acta Neurochir. Suppl. 2003, 86, 495–498.
  26. McCoy, E.; Sontheimer, H. MAPK induces AQP1 expression in astrocytes following injury. Glia 2010, 58, 209–217.
  27. Zhang, Y.; Chen, K.; Sloan, S.A.; Bennett, M.L.; Scholze, A.R.; O’Keeffe, S.; Phatnani, H.P.; Guarnieri, P.; Caneda, C.; Ruderisch, N.; et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 2014, 34, 11929–11947.
  28. Zhang, Y.; Sloan, S.A.; Clarke, L.E.; Caneda, C.; Plaza, C.A.; Blumenthal, P.D.; Vogel, H.; Steinberg, G.K.; Edwards, M.S.; Li, G.; et al. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron 2016, 89, 37–53.
  29. Srinivasan, R.; Lu, T.Y.; Chai, H.; Xu, J.; Huang, B.S.; Golshani, P.; Coppola, G.; Khakh, B.S. New Transgenic Mouse Lines for Selectively Targeting Astrocytes and Studying Calcium Signals in Astrocyte Processes In Situ and In Vivo. Neuron 2016, 92, 1181–1195.
  30. Satoh, J.; Tabunoki, H.; Yamamura, T.; Arima, K.; Konno, H. Human astrocytes express aquaporin-1 and aquaporin-4 in vitro and in vivo. Neuropathology 2007, 27, 245–256.
  31. Arcienega, I.I.; Brunet, J.F.; Bloch, J.; Badaut, J. Cell locations for AQP1, AQP4 and 9 in the non-human primate brain. Neuroscience 2010, 167, 1103–1114.
  32. Yool, A.J.; Stamer, W.D.; Regan, J.W. Forskolin stimulation of water and cation permeability in aquaporin 1 water channels. Science 1996, 273, 1216–1218.
  33. Boassa, D.; Yool, A.J. A fascinating tail: cGMP activation of aquaporin-1 ion channels. Trends Pharmacol. Sci. 2002, 23, 558–562.
  34. Boassa, D.; Yool, A.J. Single amino acids in the carboxyl terminal domain of aquaporin-1 contribute to cGMP-dependent ion channel activation. BMC Physiol. 2003, 3, 12.
  35. Boassa, D.; Stamer, W.D.; Yool, A.J. Ion channel function of aquaporin-1 natively expressed in choroid plexus. J. Neurosci. 2006, 26, 7811–7819.
  36. Tait, M.J.; Saadoun, S.; Bell, B.A.; Papadopoulos, M.C. Water movements in the brain: Role of aquaporins. Trends Neurosci. 2008, 31, 37–43.
  37. Yool, A.J.; Campbell, E.M. Structure, function and translational relevance of aquaporin dual water and ion channels. Mol. Aspects Med. 2012, 33, 553–561.
  38. Agre, P.; Lee, M.D.; Devidas, S.; Guggino, W.B. Aquaporins and ion conductance. Science 1997, 275, 1490.
  39. Deen, P.M.; Mulders, S.M.; Kansen, S.M.; van Os, C.H. Aquaporins and ion conductance. Science 1997, 275, 1491.
  40. Fischbarg, J.; Kuang, K.; Li, J.; Iserovich, P.; Wen, Q. Aquaporins and ion conductance. Science 1997, 275, 1491.
  41. Patil, R.V.; Han, Z.; Wax, M.B. Aquaporins and ion conductance. Science 1997, 275, 1492.
  42. Sasaki, S.; Uchida, S.; Kuwahara, M.; Fushimi, K.; Marumo, F. Aquaporins and ion conductance. Science 1997, 275, 1490.
  43. Verkman, A.S.; Yang, B. Aquaporins and ion conductance. Science 1997, 275, 1491.
  44. 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.
  45. Mola, M.G.; Sparaneo, A.; Gargano, C.D.; Spray, D.C.; Svelto, M.; Frigeri, A.; Scemes, E.; Nicchia, G.P. The speed of swelling kinetics modulates cell volume regulation and calcium signaling in astrocytes: A different point of view on the role of aquaporins. Glia 2016, 64, 139–154.
  46. Papadopoulos, M.C.; Saadoun, S.; Verkman, A.S. Aquaporins and cell migration. Pflug. Arch. 2008, 456, 693–700.
  47. Qi, X.T.; Zhan, J.S.; Xiao, L.M.; Li, L.; Xu, H.X.; Fu, Z.B.; Zhang, Y.H.; Zhang, J.; Jia, X.H.; Ge, G.; et al. The Unwanted Cell Migration in the Brain: Glioma Metastasis. Neurochem. Res. 2017, 42, 1847–1863.
  48. Ishibashi, K.; Sasaki, S.; Fushimi, K.; Uchida, S.; Kuwahara, M.; Saito, H.; Furukawa, T.; Nakajima, K.; Yamaguchi, Y.; Gojobori, T.; et al. Molecular cloning and expression of a member of the aquaporin family with permeability to glycerol and urea in addition to water expressed at the basolateral membrane of kidney collecting duct cells. Proc. Natl. Acad. Sci. USA 1994, 91, 6269–6273.
  49. Sasaki, S.; Ishibashi, K.; Marumo, F. Aquaporin-2 and -3: Representatives of two subgroups of the aquaporin family colocalized in the kidney collecting duct. Annu. Rev. Physiol. 1998, 60, 199–220.
  50. Yamamoto, N.; Yoneda, K.; Asai, K.; Sobue, K.; Tada, T.; Fujita, Y.; Katsuya, H.; Fujita, M.; Aihara, N.; Mase, M.; et al. Alterations in the expression of the AQP family in cultured rat astrocytes during hypoxia and reoxygenation. Mol. Brain Res. 2001, 90, 26–38.
  51. Yang, M.; Gao, F.; Liu, H.; Yu, W.H.; Zhuo, F.; Qiu, G.P.; Ran, J.H.; Sun, S.Q. Hyperosmotic induction of aquaporin expression in rat astrocytes through a different MAPK pathway. J. Cell. Biochem. 2013, 114, 111–119.
  52. Yang, M.; Gao, F.; Liu, H.; Yu, W.H.; Sun, S.Q. Temporal changes in expression of aquaporin-3, -4, -5 and -8 in rat brains after permanent focal cerebral ischemia. Brain Res. 2009, 1290, 121–132.
  53. Behrangi, N.; Lorenz, P.; Kipp, M. Oligodendrocyte Lineage Marker Expression in eGFP-GFAP Transgenic Mice. J. Mol. Neurosci. 2021, 71, 2237–2248.
  54. 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. Proc. Natl. Acad. Sci. USA 1994, 91, 13052–13056.
  55. Moe, S.E.; Sorbo, J.G.; Sogaard, R.; Zeuthen, T.; Petter Ottersen, O.; Holen, T. New isoforms of rat Aquaporin-4. Genomics 2008, 91, 367–377.
  56. Rossi, A.; Crane, J.M.; Verkman, A.S. Aquaporin-4 Mz isoform: Brain expression, supramolecular assembly and neuromyelitis optica antibody binding. Glia 2011, 59, 1056–1063.
  57. De Bellis, M.; Pisani, F.; Mola, M.G.; Basco, D.; Catalano, F.; Nicchia, G.P.; Svelto, M.; Frigeri, A. A novel human aquaporin-4 splice variant exhibits a dominant-negative activity: A new mechanism to regulate water permeability. Mol. Biol. Cell 2014, 25, 470–480.
  58. De Bellis, M.; Pisani, F.; Mola, M.G.; Rosito, S.; Simone, L.; Buccoliero, C.; Trojano, M.; Nicchia, G.P.; Svelto, M.; Frigeri, A. Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfeet localization, and water transport. Glia 2017, 65, 790–803.
  59. Neely, J.D.; Christensen, B.M.; Nielsen, S.; Agre, P. Heterotetrameric composition of aquaporin-4 water channels. Biochemistry 1999, 38, 11156–11163.
  60. Nicchia, G.P.; Mastrototaro, M.; Rossi, A.; Pisani, F.; Tortorella, C.; Ruggieri, M.; Lia, A.; Trojano, M.; Frigeri, A.; Svelto, M. Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies. Glia 2009, 57, 1363–1373.
  61. Nicchia, G.P.; Rossi, A.; Mola, M.G.; Pisani, F.; Stigliano, C.; Basco, D.; Mastrototaro, M.; Svelto, M.; Frigeri, A. Higher order structure of aquaporin-4. Neuroscience 2010, 168, 903–914.
  62. Dermietzel, R. Visualization by freeze-fracturing of regular structures in glial cell membranes. Naturwissenschaften 1973, 60, 208.
  63. Landis, D.M.; Reese, T.S. Arrays of particles in freeze-fractured astrocytic membranes. J. Cell Biol. 1974, 60, 316–320.
  64. Crane, J.M.; Verkman, A.S. Determinants of aquaporin-4 assembly in orthogonal arrays revealed by live-cell single-molecule fluorescence imaging. J. Cell Sci. 2009, 122, 813–821.
  65. Strand, L.; Moe, S.E.; Solbu, T.T.; Vaadal, M.; Holen, T. Roles of aquaporin-4 isoforms and amino acids in square array assembly. Biochemistry 2009, 48, 5785–5793.
  66. Crane, J.M.; Bennett, J.L.; Verkman, A.S. Live cell analysis of aquaporin-4 m1/m23 interactions and regulated orthogonal array assembly in glial cells. J. Biol. Chem. 2009, 284, 35850–35860.
  67. Lu, M.; Lee, M.D.; Smith, B.L.; Jung, J.S.; Agre, P.; Verdijk, M.A.; Merkx, G.; Rijss, J.P.; Deen, P.M. The human AQP4 gene: Definition of the locus encoding two water channel polypeptides in brain. Proc. Natl. Acad. Sci. USA 1996, 93, 10908–10912.
  68. Lisjak, M.; Potokar, M.; Zorec, R.; Jorgacevski, J. Indirect Role of AQP4b and AQP4d Isoforms in Dynamics of Astrocyte Volume and Orthogonal Arrays of Particles. Cells 2020, 9, 735.
  69. Potokar, M.; Stenovec, M.; Jorgacevski, J.; Holen, T.; Kreft, M.; Ottersen, O.P.; Zorec, R. Regulation of AQP4 surface expression via vesicle mobility in astrocytes. Glia 2013, 61, 917–928.
  70. Lisjak, M.; Potokar, M.; Rituper, B.; Jorgacevski, J.; Zorec, R. AQP4e-Based Orthogonal Arrays Regulate Rapid Cell Volume Changes in Astrocytes. J. Neurosci. 2017, 37, 10748–10756.
  71. Palazzo, C.; Buccoliero, C.; Mola, M.G.; Abbrescia, P.; Nicchia, G.P.; Trojano, M.; Frigeri, A. AQP4ex is crucial for the anchoring of AQP4 at the astrocyte end-feet and for neuromyelitis optica antibody binding. Acta Neuropathol. Commun. 2019, 7, 51.
  72. Sapkota, D.; Lake, A.M.; Yang, W.; Yang, C.; Wesseling, H.; Guise, A.; Uncu, C.; Dalal, J.S.; Kraft, A.W.; Lee, J.M.; et al. Cell-Type-Specific Profiling of Alternative Translation Identifies Regulated Protein Isoform Variation in the Mouse Brain. Cell Rep. 2019, 26, 594–607 e597.
  73. Albertini, R.; Bianchi, R. Aquaporins and glia. Curr. Neuropharmacol. 2010, 8, 84–91.
  74. Nielsen, S.; Nagelhus, E.A.; Amiry-Moghaddam, M.; Bourque, C.; Agre, P.; Ottersen, O.P. Specialized membrane domains for water transport in glial cells: High-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J. Neurosci. 1997, 17, 171–180.
  75. Hsu, M.S.; Seldin, M.; Lee, D.J.; Seifert, G.; Steinhauser, C.; Binder, D.K. Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus. Neuroscience 2011, 178, 21–32.
  76. Eidsvaag, V.A.; Enger, R.; Hansson, H.A.; Eide, P.K.; Nagelhus, E.A. Human and mouse cortical astrocytes differ in aquaporin-4 polarization toward microvessels. Glia 2017, 65, 964–973.
  77. Rash, J.E.; Yasumura, T.; Hudson, C.S.; Agre, P.; Nielsen, S. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc. Natl. Acad. Sci. USA 1998, 95, 11981–11986.
  78. Nagelhus, E.A.; Mathiisen, T.M.; Ottersen, O.P. Aquaporin-4 in the central nervous system: Cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience 2004, 129, 905–913.
  79. Pan, Q.L.; Lin, F.X.; Liu, N.; Chen, R.C. The role of aquaporin 4 (AQP4) in spinal cord injury. Biomed. Pharmacother. 2022, 145, 112384.
  80. Nicchia, G.P.; Rossi, A.; Mola, M.G.; Procino, G.; Frigeri, A.; Svelto, M. Actin cytoskeleton remodeling governs aquaporin-4 localization in astrocytes. Glia 2008, 56, 1755–1766.
  81. Solenov, E.; Watanabe, H.; Manley, G.T.; Verkman, A.S. Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am. J. Physiol. Cell Physiol. 2004, 286, C426–C432.
  82. Raina, S.; Preston, G.M.; Guggino, W.B.; Agre, P. Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues. J. Biol. Chem. 1995, 270, 1908–1912.
  83. King, L.S.; Kozono, D.; Agre, P. From structure to disease: The evolving tale of aquaporin biology. Nat. Rev. Mol. Cell Biol. 2004, 5, 687–698.
  84. Ma, T.; Song, Y.; Gillespie, A.; Carlson, E.J.; Epstein, C.J.; Verkman, A.S. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J. Biol. Chem. 1999, 274, 20071–20074.
  85. McCoy, E.; Sontheimer, H. Expression and function of water channels (aquaporins) in migrating malignant astrocytes. Glia 2007, 55, 1034–1043.
  86. Yang, M.; Gao, F.; Liu, H.; Yu, W.H.; He, G.Q.; Zhuo, F.; Qiu, G.P.; Sun, S.Q. Immunolocalization of aquaporins in rat brain. Anat. Histol. Embryol. 2011, 40, 299–306.
  87. Foo, L.C.; Allen, N.J.; Bushong, E.A.; Ventura, P.B.; Chung, W.S.; Zhou, L.; Cahoy, J.D.; Daneman, R.; Zong, H.; Ellisman, M.H.; et al. Development of a method for the purification and culture of rodent astrocytes. Neuron 2011, 71, 799–811.
  88. Wolfes, A.C.; Ahmed, S.; Awasthi, A.; Stahlberg, M.A.; Rajput, A.; Magruder, D.S.; Bonn, S.; Dean, C. A novel method for culturing stellate astrocytes reveals spatially distinct Ca2+ signaling and vesicle recycling in astrocytic processes. J. Gen. Physiol. 2017, 149, 149–170.
  89. Badaut, J.; Lasbennes, F.; Magistretti, P.J.; Regli, L. Aquaporins in brain: Distribution, physiology, and pathophysiology. J. Cereb. Blood Flow Metab. 2002, 22, 367–378.
  90. King, L.S.; Agre, P. Pathophysiology of the aquaporin water channels. Annu. Rev. Physiol. 1996, 58, 619–648.
  91. Ishibashi, K.; Kuwahara, M.; Kageyama, Y.; Tohsaka, A.; Marumo, F.; Sasaki, S. Cloning and functional expression of a second new aquaporin abundantly expressed in testis. Biochem. Biophys. Res. Commun. 1997, 237, 714–718.
  92. Oshio, K.; Binder, D.K.; Yang, B.; Schecter, S.; Verkman, A.S.; Manley, G.T. Expression of aquaporin water channels in mouse spinal cord. Neuroscience 2004, 127, 685–693.
  93. La Porta, C.A.; Gena, P.; Gritti, A.; Fascio, U.; Svelto, M.; Calamita, G. Adult murine CNS stem cells express aquaporin channels. Biol. Cell 2006, 98, 89–94.
  94. Gao, Y.; Deng, Q.; Zhang, Y.; Zhang, S.; Zhu, Y.; Zhang, J. The expression of the multiple splice variants of AQP8 in porcine testes at different developmental stages. J. Appl. Genet. 2014, 55, 511–514.
  95. 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, but not to glycerol. Biochem. Biophys. Res. Commun. 1998, 244, 268–274.
  96. Liu, Y.; Promeneur, D.; Rojek, A.; Kumar, N.; Frokiaer, J.; Nielsen, S.; King, L.S.; Agre, P.; Carbrey, J.M. Aquaporin 9 is the major pathway for glycerol uptake by mouse erythrocytes, with implications for malarial virulence. Proc. Natl. Acad. Sci. USA 2007, 104, 12560–12564.
  97. Ohgusu, Y.; Ohta, K.Y.; Ishii, M.; Katano, T.; Urano, K.; Watanabe, J.; Inoue, K.; Yuasa, H. Functional characterization of human aquaporin 9 as a facilitative glycerol carrier. Drug. Metab. Pharm. 2008, 23, 279–284.
  98. Rojek, A.M.; Skowronski, M.T.; Fuchtbauer, E.M.; Fuchtbauer, A.C.; Fenton, R.A.; Agre, P.; Frokiaer, J.; Nielsen, S. Defective glycerol metabolism in aquaporin 9 (AQP9) knockout mice. Proc. Natl. Acad. Sci. USA 2007, 104, 3609–3614.
  99. Papadopoulos, M.C.; Verkman, A.S. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci. 2013, 14, 265–277.
  100. Amiry-Moghaddam, M.; Lindland, H.; Zelenin, S.; Roberg, B.A.; Gundersen, B.B.; Petersen, P.; Rinvik, E.; Torgner, I.A.; Ottersen, O.P. Brain mitochondria contain aquaporin water channels: Evidence for the expression of a short AQP9 isoform in the inner mitochondrial membrane. FASEB J. 2005, 19, 1459–1467.
  101. Badaut, J.; Brunet, J.F.; Petit, J.M.; Guerin, C.F.; Magistretti, P.J.; Regli, L. Induction of brain aquaporin 9 (AQP9) in catecholaminergic neurons in diabetic rats. Brain Res. 2008, 1188, 17–24.
  102. Tsukaguchi, H.; Shayakul, C.; Berger, U.V.; Mackenzie, B.; Devidas, S.; Guggino, W.B.; van Hoek, A.N.; Hediger, M.A. Molecular characterization of a broad selectivity neutral solute channel. J. Biol. Chem. 1998, 273, 24737–24743.
  103. Tsukaguchi, H.; Weremowicz, S.; Morton, C.C.; Hediger, M.A. Functional and molecular characterization of the human neutral solute channel aquaporin-9. Am. J. Physiol. 1999, 277, F685–F696.
  104. Badaut, J.; Hirt, L.; Granziera, C.; Bogousslavsky, J.; Magistretti, P.J.; Regli, L. Astrocyte-specific expression of aquaporin-9 in mouse brain is increased after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2001, 21, 477–482.
  105. 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.
  106. Badaut, J.; Brunet, J.F.; Guerin, C.; Regli, L.; Pellerin, L. Alteration of glucose metabolism in cultured astrocytes after AQP9-small interference RNA application. Brain Res. 2012, 1473, 19–24.
  107. Mylonakou, M.N.; Petersen, P.H.; Rinvik, E.; Rojek, A.; Valdimarsdottir, E.; Zelenin, S.; Zeuthen, T.; Nielsen, S.; Ottersen, O.P.; Amiry-Moghaddam, M. Analysis of mice with targeted deletion of AQP9 gene provides conclusive evidence for expression of AQP9 in neurons. J. Neurosci. Res. 2009, 87, 1310–1322.
  108. Lindskog, C.; Asplund, A.; Catrina, A.; Nielsen, S.; Rutzler, M. A Systematic Characterization of Aquaporin-9 Expression in Human Normal and Pathological Tissues. J. Histochem. Cytochem. 2016, 64, 287–300.
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