News Physiol Sci 17: 68-72, 2002;
1548-9213/02 $5.00
News in Physiological Sciences, Vol. 17, No. 2, 68-72,
April 2002
© 2002 Int. Union Physiol. Sci./Am. Physiol. Soc.
New Roles for Old Holes: Ion Channel Function in Aquaporin-1
Andrea J. Yool1 and
Alan M. Weinstein2
1 Department of Physiology, Department of Pharmacology, University of Arizona College of Medicine, Tucson Arizona 85724-5051;
2 Department of Physiology, Weill Medical College of Cornell University, New York, New York 10021-4896
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Abstract
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Mammalian aquaporins are part of the diverse major intrinsic protein family of water and solute channels. Intriguing links exist in structural and functional properties between aquaporins and ion channels. A novel role for aquaporin-1 as a gated ion channel reshapes our current views of this ancient family of transmembrane channel proteins.
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Introduction
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Aquaporin-1 (AQP1) channels associate as tetramers of identical subunits in a structural organization reminiscent of the ion channel gene family, including K+ channels and cyclic nucleotide-gated (CNG) channels (9). Ion channels use a central pore in the middle of the tetramer of subunits as a pathway for gated ion flux. In K+ channels, the central pore is lined in part by the segment linking transmembrane domains 5 and 6. The analogous central region of AQP1 is lined by transmembrane domains 2 and 5. The central region of glycerol facilitator (GlpF), a glycerol-conducting member of the aquaporin family, shows a capacity for ion binding that suggests that a pore may exist at the fourfold axis of symmetry in regulated aquaporins (7).
The existence of selective water channels in biological membranes was postulated on the basis of physiological evidence decades before the first molecular identification of aquaporins. Cloning and characterization of major intrinsic protein (MIP) channels launched new interest in proteins involved in transmembrane water transport. Several members of the MIP family have been shown to function as ion channels, including AQP0, AQP1, AQP6, and soybean Nodulin 26. Other mammalian members of the MIP family may also function as ion channels when activated by an appropriate, as yet unidentified stimulus.
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Similar structural themes for AQP1 and K+ channels
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The first characterization of AQP1 as a cation channel (19) was initially disputed; however, subsequent work has shown that the cationic conductance of AQP1 is directly gated by cGMP binding when expressed inXenopus oocytes (1), a finding confirmed with AQP1 channels reconstituted in lipid bilayers (15). AQP1 is a nonselective cation channel permeant to K+, Cs+, and Na+ and to a lesser degree tetraethylammonium (TEA) (19). The AQP1 carboxy tail domain has sequence similarity with the cyclic nucleotide binding domains of CNG channels that suggested direct ligand binding, an idea confirmed by several lines of evidence (1). In oocytes, AQP1 channels show a large conductance (~150 pS) in excised inside-out patches when exposed to cGMP but not cAMP (1). Bilayers are a useful experimental system but cannot offer the complex environment of a eukaryotic cell. AQP1 channels reconstituted in bilayers show a lower unitary conductance and a lower proportion of active channels but retain the essential properties of cation selectivity, dependence on cGMP not cAMP, and reliance on an intact carboxy tail domain for ion channel activation (15). The channel conductance states for AQP1 reconstituted in bilayers are 2.4, 5.9, and 9.8 pS (15). These differences in AQP1 function in oocytes and bilayers may provide clues to additional contributions of cytoskeletal associations, regulatory proteins, or second messengers that modulate channel properties. The ability of AQP1 to interact with another signaling molecule was demonstrated for the ephrin receptor tyrosine kinase EphB2, which forms a stable macromolecular complex with AQP1 in kidney that is mediated by PDZ domains (a consensus sequence involved in many selective protein-protein interactions) (3). The association of AQP1 with other signaling molecules reinforces the idea that these proteins may be subject to multiple levels of regulation and signaling hierarchies that may moreover depend on distinct local cytosolic environments. It is becoming increasingly clear that the original conception of AQP1 channels as constitutively open holes, unregulated but spectacular in their exclusive permeability to water, was a reasonable starting point but in retrospect naive. AQP1 is now emerging as a complex, sophisticated, and regulated protein with multiple functional capacities.
Crystal structures of the central pore domains of the two channel classes are illustrated in Fig. 1
and show the general similarities in structure. The central pore in the K+ channel (KcsA) is a large, water-filled cavity with the narrowest region being at the selectivity filter near the external side, where K+ ions are stripped of their shells of hydration to pass (5). This precisely tuned selectivity filter is capable of selecting for K+ over Na+ions at a ratio of at least 10,000 to 1 by taking advantage of differences in energies of hydration. In Fig. 1B, tyrosine (Y78) and glycines (G77and G79), corresponding to the GYG selectivity filter for K+channels (8), are highlighted. The adjacent negatively charged aspartate (D80) is also shown. Both the intracellular and extracellular entryways of the K+ channel are lined by acidic residues, thought to attract an increased local concentration of cations. The large central cavity (10-Å diameter) is proposed to help overcome an electrostatic energy barrier for cations that is maximal at the midpoint of the membrane by allowing them to remain hydrated in transit to the selectivity filter. With the exception of the selectivity filter, the lining of the K+channel pore is mainly hydrophobic, perhaps contributing a relatively inert surface that allows the characteristically high throughput rates for ion flow.
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FIGURE 1. Models of the central pore of aquaporin-1 (AQP1) and the KcsA K+ channel show general similarities in structure. Structural models for AQP1 (#1FQY) and KcsA (#1F6G) were created with RasMol software using information from the NIH Protein Database. A: regions of AQP1 (13) that interface at the central fourfold axis of symmetry are viewed from the extracellular side. Shown are amino acids 36–66 in the second transmembrane helix (M2) and amino acids 167–189 in the fifth transmembrane helix (M5) and flanking regions. Highlighted residues are Gln47 (violet), Asp48 (white), and Val50 (orange). B: the KcsA K+ channel (5) has a central pore highly selective for K+ ions and 2 transmembrane helices per subunit. The channel is viewed from the extracellular side. Highlighted residues are Gly77 (orange), Tyr78 (violet), and Gly79 (orange), forming the signature sequence of K+ channels (8), with an adjacent Asp80 (white). C: cartoon illustration of a hypothetical 5-pore model for AQP1, showing individual water channels in each subunit of the tetramer and a putative central pore for ions in the center of the tetramer.
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The central passage in AQP1 is lined by transmembrane helices M2 and M5 (Fig. 1
A). A fourfold symmetry of glutamine (Q47) or valine (V50) residues in M2 creates the narrowest constriction on the external side, ~3-Å diameter (13,14). A negatively charged residue (D48) is located adjacent to Q47. The residues Q47, D48, and valine (V50) are highlighted. As in the K+ channels, the central pore of AQP1 is narrowest on the external side, is largely hydrophobic, and has a large central cavity near the membrane midpoint (13). A hydrophobic lining in the larger regions of the central pore is consistent with ion permeation; the K+ channel shows a similar design. Furthermore, AQP1 has been imaged without cGMP, so apparent hydrophobic barriers may instead represent regulated gating sites. To truly assess the potential of the central pore as an ionic pathway, AQP1 channels would have to be imaged in the presence of cGMP agonist.
A GYG selectivity filter sequence is not present in the central pore of AQP1. This correlates with the lack of ionic selectivity seen for activated AQP1 ion channels, which, unlike K+ channels, are also permeant to Na+ and TEA (19). Given this nonselective cation permeability, the ionic selectivity filter for AQP1 might be expected to be relatively simple in design, without requiring the precise arrangement of carbonyl groups that allow for K+ dehydration in the K+ channel. If ion flow is mediated by the central pathway, then one might speculate that channel opening must be accompanied by a conformational change that effectively increases the limiting size of the pore to accommodate TEA.
The TEA ion is permeant through activated AQP1 ion channels (19) but blocks osmotic water permeability (2). These findings are consistent with the proposal that AQP1 has a "five-pore structure" with four parallel pathways for water and one for cations (Fig. 1C). Constitutive water flux probably occurs through individual pores present in each of the four subunits. The site mediating TEA block is tyrosine (Y186) (2) located near the mercury-binding cysteine (C189) in the water-conducting pathway. The previously proposed role of individual subunits as pores for water in AQP1 is supported by recent crystal structure analysis of the related MIP protein GlpF that showed glycerol molecules lined up in transport pathways within each individual subunit (7). The proposed single central pore for ions is consistent with an established theme in the family of ion channels and corroborated by patch clamp studies of AQP1 showing unitary events (1) rather than obligatory multilevel events of equal conductance that might be expected to arise from clusters of elementary pores. Additional support for a central ion pore stems from the identification of Mg2+ ion binding sites in the central region of GlpF (7).
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Cyclic nucleotide binding site in the carboxy terminal domain
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The carboxy tail domain of AQP1 shows a pattern of amino acid sequence similarity with CNG channel carboxy domains (1) in a region that has been shown in mutagenesis studies to be involved in cyclic nucleotide binding and channel activation (Fig. 2). The amino acid sequence alignment provides support for the existence of a cyclic nucleotide binding domain in each subunit of the AQP1 channel. Deletion of the carboxy terminal domain removes cGMP-dependent ion channel function (15). Carboxy tail domains of other MIP channels show a variety of sequence patterns, but most lack the cGMP consensus-like domain (18). Systematic sequence comparisons with ion channels and enzymes, as well as tests of various second messenger cascades, may provide clues for linking structure with regulated functions in other AQP channels.
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FIGURE 2. Amino acid sequence similarities between the carboxy tail domains of cyclic nucleotide gated (CNG) channels and AQP1. Sequence similarities exist between the carboxy tail domains of AQP1 and CNG channels in a region that contributes to cyclic nucleotide binding. The complete sequence of the AQP1 carboxy terminal corresponds to only part of that of CNG channels; other CNG channel regions also contribute to cyclic nucleotide binding and channel activation. Red text on yellow shows residues conserved between AQP1 and CNG channels. Black text on turquoise highlights residues that are similar but shifted in position. Sequence alignments were assisted by a NCBI Protein-Protein BLAST analysis.
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The activation of ionic permeability in AQP1-expressing oocytes requires intracellular signaling, whereas water permeability is a feature of both the stimulated and unstimulated states (19). Forskolin (a stimulator of adenylate cyclase and cAMP signaling) showed a variable efficacy in stimulating the AQP1 conductance response (19). However, direct injection of the catalytic subunit of protein kinase A (PKA) reliably generated the ionic conductance response with a latency shorter than that of forskolin. The action of PKA may be through an indirect mechanism that upregulates cGMP levels or that involves an associated protein (such as a kinase or cytoskeletal protein), which in turn modulates AQP1 ion channel function (Fig. 3). Three other factors are implicated in the variability of the response to forskolin: 1) variable retention of follicular cells in oocyte preparation may affect the magnitude of cAMP accumulation and thus PKA stimulation in the oocyte (12); 2) cAMP may act as a poor agonist or antagonist of AQP1 channels; and 3) the cGMP-dependent activation of AQP1 as an ion channel is influenced by membrane potential (1), as are the retinal CNG channels (10).
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FIGURE 3. Schematic diagram of possible signaling cascades involved in the activation of ion channel function in AQP1 expressed in Xenopus oocytes. AQP1 channels are constitutively permeant to water (blue arrows) but show a cGMP-dependent cationic conductance that allows Na+ entry (red arrow). Forskolin-sensitive adenylate cyclase (AdCyc) is expressed in follicular cells that communicate with the oocyte via gap junctions. Stimulation of ion channel function by cAMP or protein kinase A (PKA) is blocked by kinase inhibitor H7, whereas the effect of cGMP is by direct binding and is H7 insensitive. Excess levels of cAMP may antagonize the response; thus the effectiveness of forskolin as an activator of AQP1 ion channels may depend on the relative levels of signaling molecules within a cascade of cross-talk pathways.
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Possible significance of AQP1 ion channel function
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It is natural to consider the significance of the conductive properties of AQP1 in a transporting epithelium in which the channel is abundant. The proximal tubule of the mammalian kidney reabsorbs about two-thirds of filtered water and solutes or the equivalent of three to four times its cellular volume every minute (reviewed in Ref. 17). A schematic of the proximal tubule cell is depicted in Fig. 4, showing the important solute pathways across luminal and peritubular membranes. The principal pathway for Na+ entry is an electroneutral Na+/H+ exchanger, which by itself mediates net reabsorption of NaHCO3 and, when functioning in parallel with a Cl-/HCO3- exchanger, mediates net reabsorption of NaCl. Electrophysiology of rat proximal tubule has indicated a relatively high resistance of luminal membrane (260 
•cm2), exclusively cation conductive, with a high selectivity for K+ (reviewed in Ref. 6). The peritubular membrane contains the metabolically driven Na+ exit step (Na+-K+-ATPase), an electrogenic Na+-3HCO3- cotransporter, and two important pathways for neutral Cl- exit (K+-Cl- cotransport and Na+-dependent Cl-/HCO3- exchange). The resistance of a peritubular cell membrane is lower (90 •cm2), and again the conductive pathway is primarily a K+ channel, although under certain conditions it appears that a Cl- channel emerges. Both luminal and peritubular membranes contain AQP1 in abundance sufficient to account for all of the tubule water permeability (11).
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FIGURE 4. Schematic of solute transport pathways across a proximal tubule cell. Luminal membrane transporters include the Na+-glucose cotransporters (SGLT1 and SGLT2), the Na+/H+ exchanger (NHE3), the Na+-HPO42– cotransporter (NaPi2), an unidentified Cl-/base exchanger (AE), and a K+ channel. Peritubular membrane transporters include the Na+-K+-ATPase, the K+-Cl- cotransporter (KCC), the Na+-3HCO3- cotransporter (NBC1), and the Na+-dependent Cl-/HCO3- exchanger (NDCBE), as well as K+ and Cl- channels. High water permeability is mediated by AQP1 channels, which after cGMP stimulation may also increase Na+entry. The tight junctions of proximal tubules allow substantial and relatively nonselective fluxes of cations and anions.
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The biophysical data regarding the conductance of the cGMP-activated AQP1 suggest that its impact on proximal tubule function could be meaningful. Both luminal and peritubular cell membranes have comparable areas (36 cm2 membrane/cm2 epithelium) and specific water permeabilities (Pf = 0.015 cm/s). A value for the unitary channel water permeability of 1.20 x 10-13 cm/s implies a channel density of 4.50 x 1012/cm2 epithelium. If cGMP renders only 1/56,000 of these channels conductive (1), then the unitary conductance of 145 pS translates into a total conductance of 12 mS/cm2 epithelium, comparable to the native conductance of peritubular membrane. Model-based calculations suggest that if such a conductance (with equal Na+ and K+ permeabilities) were to appear only in the luminal membrane of the proximal tubule, it could mediate a 45% increase in cell Na+ entry (an 18% increase in overall epithelial Na+ reabsorption), along with a –2 mV change in epithelial potential difference from a baseline of –0.4 mV. Concomitant peritubular activation of a similar conductance would slightly blunt these effects. Although the effect of cGMP on proximal tubule has not been studied extensively, addition of either cGMP or sodium nitroprusside to microperfused rat tubules has yielded 50% increases in volume (equivalently Na+) reabsorption (16), whereas inhibition of nitric oxide (NO) synthase resulted in a 47% decrease in volume reabsorption (4). These observations are attractive in the sense that the humoral signal (NO) that enhances glomerular filtration also enhances proximal reabsorption, thus helping to maintain glomerulotubular balance. It is questionable, however, whether the tubular effect is mediated by the appearance of a cation channel, since in this same study proximal HCO3- absorption increased in parallel with the enhanced volume flux, suggesting an effect of NO on the Na+/H+ exchanger (16). It will be important to complement these findings with an electrophysiological study of cGMP effects on proximal tubule.
AQP1 may subserve mechanisms of water regulation that involve receptor signaling mechanisms and ion fluxes that would not be possible with a constitutively active and strictly water-selective channel. Given the structure of the individual subunit pores for water in AQP1, ion permeation through the individual subunit pathways seems unlikely, but one can speculate that ions and water might interact in the entryways to the conduction pathways or in the central pore if it is permeant to both water and ion fluxes. The regulation of cation permeability of AQP1 through a cGMP-dependent signaling cascade has potential importance to the control of secretion and absorption of fluid, as well as to regulation of cell volume, in many tissues that express this channel at high levels.
In summary, the discovery of ion channel function in aquaporins has potential significance to basic and clinical research involving the regulated control of water and ion fluxes across membranes. Ion channel electrophysiological studies have added new breadth to our understanding of the fundamental properties of this important class of channels and have established a new direction for research in this field.
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Acknowledgments
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Thanks to Susan Sotardi and Dr. Alex Simon, University of Arizona, for assistance and helpful discussions and to all of the members of the lab for their research contributions.
This work was supported by National Institutes of Health Grants RO1-GM-59986 (A. J. Yool) and RO1-DK-29857 (A. M. Weinstein).
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Introduction
Similar structural themes for...
