Frontiers in Nephrology: Renal Sodium Handling: The Role of the Epithelial Sodium Channel
Acute Regulation of Epithelial Sodium Channel by Anionic Phospholipids
He-Ping Ma* and
Douglas C. Eaton
* Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Alabama; Department of Physiology, Emory University of School of Medicine, Atlanta, Georgia
Address correspondence to: Dr. He-Ping Ma, Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, 1530 Third Avenue South, Sparks Center 865, Birmingham, AL 35294. Phone: 205-934-3806; Fax: 205-934-1147; E-mail: hepingma{at}uab.edu
Anionic phospholipids such as phosphatidylinositol 4,5-bisphosphate(PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) arenormally located in the inner leaflet of the plasma membrane,where these anionic phospholipids can regulate transmembraneproteins, including ion channels and transporters. Recent workhas demonstrated that (1) ATP inhibits the renal epithelialsodium channel (ENaC) via a phospholipase C–dependentpathway that reduces PIP2, (2) aldosterone stimulates ENaC viaphosphoinositide 3-kinase, and (3) PIP2 and PIP3 regulate ENaC.Several lines of evidence show that ATP stimulation of purinergicP2Y receptors hydrolyzes PIP2 and that aldosterone stimulationof steroid receptors induces PIP3 formation. These studies togethersuggest that one primary mechanism for regulating ENaC is byalteration of anionic phospholipids and that the receptor-mediatedand hormonal regulation of ENaC works through a variety of signalingpathways, but many of these pathways finally alter ENaC activityby regulating the formation or degradation of anionic phospholipids.Therefore, changes in the concentration of PIP2 and PIP3 arehypothesized to participate in the regulation of ENaC by purinergicand corticoid receptors. The underlying mechanism may be associatedwith a physical interaction of the positively charged cytoplasmicdomains of the - and -ENaC with the negatively charged membranephospholipids. The exact nature of this interaction will requirefurther investigation.
The phospholipid compositions of the two leaflets of the lipidbilayer that forms the plasma membrane are strikingly different.Anionic phospholipids are normally located in the inner leafletto form a negatively charged surface. However, whether the phospholipidasymmetry affects the function of transmembrane proteins remainslargely unknown. Recent studies have shown that one of the anionicphospholipids, phosphatidylinositol 4,5-bisphosphate (PIP2),regulates Na+-Ca2+ exchangers and inward rectifier potassiumchannels (1–4). Besides PIP2, phosphatidylinositol 3,4,5-trisphosphate(PIP3), regulates ATP-sensitive potassium (KATP) channels (5,6).A model for the regulation of KATP channels by anionic phospholipidshas been proposed; the negatively charged head group of PIP2or PIP3 locks the positively charged carboxyl terminus of KATPchannels in an open conformation and prevents ATP binding tothe cytosolic terminus (7). These recent studies suggest thatanionic phospholipids may interact with the positively chargedcytoplasmic termini of other ion channels and transporters.In this review, we focus primarily on the mechanism by whichchanges in cellular anionic phospholipids such as PIP2 and PIP3regulate the renal epithelial sodium channel (ENaC) and thenspeculate on a possible underlying mechanism.
Stimulation of Purinergic P2Y Receptors Decreases Membrane PIP2 and ENaC Activity
It is known that ATP binds to the purinergic P2Y receptor family,G protein–coupled receptors that activate phospholipaseC (PLC) to hydrolyze PIP2, resulting in a decrease in PIP2 concentrationin the inner leaflet of the plasma membrane. P2Y receptors,particularly the P2Y2 receptor, are expressed in renal tissues(8–11). ATP binding to the P2Y2 receptor inhibits Na+absorption in mouse cortical collecting duct principal cells(10). Our recent studies show that ATP inhibits the activityof ENaC via a PLC-dependent pathway in A6 distal nephron cells(12). These studies suggest that ENaC is regulated by purinergicP2Y receptors. The traditional signaling pathway after G protein–coupledreceptor activation of PLC involves the breakdown of PIP2 toform inositol 1,4,5-trisphosphate (IP3) and diacylglycerol,which together lead to increases in intracellular Ca2+ and activationof protein kinase C (PKC). One or the other of these then isthought to produce the final effect on ENaC activity after receptorstimulation. Thus, PIP2 is often considered to be nothing morethan a substrate for PLC with the metabolic products being theimportant signaling molecules.
Although there is little question that activation of PKC canalter ENaC activity (13–17), our work has shown that ENaCis also directly regulated by PIP2 (18,19). We demonstratedthat PIP2 added to the cytosolic surface maintains ENaC activityin inside-out patches. In contrast, both sequestration of endogenousPIP2 with anti-PIP2 antibody and hydrolysis of PIP2 after activationof endogenous PLC or addition of exogenous PLC reduced channelactivity. When expressed in Xenopus oocytes, ENaC is stimulatedby cytosolic injection of PIP2 (18). These observations suggestan additional and alternative mechanism for P2Y2 receptor regulationof ENaC in which activation of PLC reduces PIP2 concentrationand the reduction in PIP2 (rather than the production of IP3and diacylglycerol) causes the reduction in ENaC activity. Therefore,a decrease in PIP2 concentration induced by purinergic receptoractivation may account for some of the inhibition of ENaC byATP. As mentioned above, there is ample evidence that when PKCis activated, ENaC is inhibited, and when PKC is inhibited,ENaC is activated. However, the phosphorylation target for PKChas remained elusive. The best evidence suggests that Ca2+ inhibitsENaC in intact cells but does not inhibit ENaC in excised inside-outpatches (17) and that PKC inhibits ENaC in A6 cells (17) butdoes not phosphorylate ENaC (20). Furthermore, at least in oocytes,when PKC is activated with phorbol ester, membrane levels ofPIP2 decrease and PIP2-dependent inward rectifier potassiumchannel activity is reduced (21,22). These results suggest thatPKC may also regulate ENaC by alteration of PIP2, but furtherinvestigation will be required to determine whether this isthe mechanism for PKC inhibition of ENaC.
Stimulation of Steroid Receptors Increases Membrane PIP3 and ENaC Activity
Besides PIP2, PIP3 regulates KATP channels (5,6) and other inwardrectifier potassium channels (23–25). However, its rolehas not attracted as much attention because, under normal conditions,basal PIP3 levels are very low in cells, even though it is wellknown that PIP3 can be generated from PIP2 by activation ofphosphotidylinositol-3-kinase (PI 3-K). Recent studies suggestthat both aldosterone and insulin enhance Na+ transport by activatingPI 3-K in A6 cells (26–28) and that the concentrationof PIP3 in A6 cells is elevated in response to aldosterone (26).Recent studies have also shown that not only PIP2 but also otheranionic phospholipids, including PIP3, acutely regulate ENaCactivity in A6 cells (18,29). Aldosterone stimulates ENaC intwo phases: An acute phase, which is associated with the elevationof channel open probability, and a chronic phase, which is possiblyrelated to an increase in cell surface expression of ENaC (30–35).Because PIP3 acutely increases ENaC open probability (29), PIP3formation may mediate some or all of the acute effect of aldosteroneon ENaC open probability.
However, anionic phospholipids, particularly inositol lipidsphosphorylated at the 3 position, are also involved in vesicletrafficking to the plasma membrane (36–39). For example,a PI 3-K inhibitor (wortmannin) and dominant-negative PI 3-Kblock the insulin-mediated translocation of GLUT4 glucose transporterto the plasma membrane (40,41). Therefore, besides acutely increasingENaC open probability, PIP3 may mediate at least part of thechronic effect of aldosterone on ENaC cell surface expression.Because insulin also elevates ENaC activity via PI 3-K (28,42),PIP3 likely also mediates the regulation of ENaC by insulin(43,44).
Are There Any Consensus Sequences for PIP2 and PIP3 Binding?
Almost a decade has passed since PIP2 was found to regulatemembrane proteins such as the Na/Ca exchanger and inward rectifierpotassium channels. However, no simple consensus sequence forPIP2 binding has been identified. Although pleckstrin homology(PH) domains have been described in >100 proteins, a carefulBLAST search reveals that there is no strict homology betweenthese domains. This may not be surprising because x-ray crystallographicstudies suggest that a three-dimensional structure is requiredfor specific recognition of phosphoinositides (45). Despitethat phosphoinositide binding sites have no universal consensussequence, one common feature of these PH domains is that allof them contain significant numbers of positively charged lysinesor arginines, and it is generally accepted that PIP2 or PIP3binding is closely associated with these positively chargedlysine and arginine residues. Therefore, any proteins that containrepeating lysine- or arginine-rich motifs may bind phosphoinositidesand be regulated by PIP2 and PIP3 even though there is no commonconsensus sequence for the binding domains (45).
Despite that most of the domains were found to bind phospholipidswith high affinity but low selectivity (46), two exceptionsare the PH domain of PLC1 (PLC1-PH domain) and the PH domainof the general receptor for phosphoinositides-1 (GRP1-PH domain),which respectively bind to PIP2 and PIP3 with high affinityand high selectivity. The GRP1-PH domain selects PIP3 over PIP2by >100-fold (37,47). To determine the molecular basis thataccounts for the different binding affinity, the sequences ofPLC1-PH (Figure 1A) and GRP1-PH (Figure 1B) domains were comparedas shown in Figure 1. By comparing the positions of positivelycharged lysine (K) and arginine (R) between the PLC1-PH domainand the GRP1-PH domain, it seems that positively charged K andR in the PLC1-PH domain are usually separated by other aminoacids. Conversely, positively charged K and R in the GRP1-PHdomain are close to each other. Using synthesized peptides,it has been shown that insertion of a K between two Ks abolishesPIP2 binding (48). Previous crystallography studies also suggestthat a specific three-dimensional structure is required forselective phosphoinositol binding (45,49,50). However, whethergeometric localization of positively charged amino acids isimportant for the selectivity of PIP2 and PIP3 binding is notcompletely clear.
Figure 1. Amino acid sequences of phospholipase C 1 pleckstrin homology (PLC-1-PH) domain (A) and general receptor for phosphoinositides-1 PH (GRP1-PH) domain (B). Under physiologic conditions (pH 7.4), K and R residues contain positive charges, whereas D and E residues contain negative charges. Both positive and negative charges were marked under each amino acid. Putative phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) binding motifs are shown in bold.
Cytoplasmic Domains of - and -ENaC Contain Possible PIP2 and PIP3 Binding Motifs
ENaC consists of three subunits designated , , and (51). Byanalyzing the sequences of cytoplasmic domains of ENaC, severalpositively charged lysine- or arginine-rich motifs are consistentlyfound in the cytoplasmic domains (especially N-termini, as shownin Figure 2) of - and -ENaC among all species including human,rat, mouse, and Xenopus. It is known that the C-termini of -and -ENaC play an important role in regulating ENaC activity.Recent studies have also shown that deletion of the cytoplasmicN-termini of - (2 to 49) and -ENaC (2 to 53) but not the homologousN-terminal section of -ENaC (2 to 46) dramatically reduces ENaCactivity (52), suggesting that the N-termini of - and -ENaCalso regulate ENaC activity. Therefore, PIP2 and PIP3 may regulateENaC by interacting with its cytoplasmic domains at arginine-or lysine-rich regions and that these lysine- or arginine-richmotifs may represent the specific binding sites for both PIP2and PIP3.
Figure 2. Amino acid sequences of the N-termini of -subunit (A) and -subunit (B) of epithelial sodium channel (ENaC). Under physiologic conditions (pH 7.4), K and R residues contain positive charges, whereas D and E residues contain negative charges. Both positive and negative charges were marked under each amino acid. Possible PIP2 and PIP3 binding motifs are shown in bold.
Possible Role of PIP2 and PIP3 in Receptor-Mediated ENaC Regulation
Many hormones and transmitter agents alter ENaC activity inrenal epithelial cells. These include such diverse agents asadenosine (53), dopamine (54), angiotensin II (55), insulin(56), prostaglandin E2 (57), purinergic agents (12), and aldosterone(31). Anionic phospholipids also regulate ENaC open probability(18,19). Any agent that regulates the membrane levels (by degradationor synthesis) of these lipids should regulate ENaC. Any anionicphospholipid in theory can produce this regulation, but thenaturally occurring lipids PIP2 and PIP3 seem to be the mostimportant. Because the production and degradation of each lipidare under the control of separate enzymes, they can be differentiallyregulated to produce varying physiologic responses. In thisreview, we have focused on two specific examples: One is relatedto a decrease in PIP2 caused by P2Y receptor–induced activationof PLC; the other is associated with an increase in PIP3 causedby steroid receptor–induced activation of PI 3-K.
Previous studies have shown that the PH domain of PLC1 bindsto both PIP2 and IP3 (50,58) and that the level of PIP2 in theplasma membrane and the production of IP3 can be visualizedby the green fluorescent protein–tagged PH domain of PLC1(59). Using this method, it was shown recently that PIP2 hydrolysismediates EGF-induced inhibition of ENaC (60). We recently demonstratedthat a decrease in membrane PIP2 accounts for ENaC inhibitioninduced by both purinergic receptor activation and ionomycin-inducedelevation of intracellular calcium (61). Our studies have shownthat PIP2 binds to both - and -ENaC subunits (19), even thoughthe binding sites for PIP2 have not been identified yet. Asa hypothesis, we propose a working model in which ATP causesa loss of negative charges (PIP2) on the inner surface of plasmamembrane and thereby releases the positively charged cytoplasmicdomains that lead to decreases in ENaC open probability, asshown in the top part of Figure 3.
Figure 3. Working models for ENaC regulation by either ATP via a decrease in membrane PIP2 or aldosterone via an increase in membrane PIP3. Under resting conditions, the positively charged regions of the cytoplasmic termini of - and -ENaC are held in a certain position by the negatively charged PIP2 located in the inner leaflet of plasma membrane (top left). When luminal ATP is elevated, the concentration of PIP2 is decreased as a result of the activation of PLC via P2Y receptors. Loss of PIP2"unlocks" the cytoplasmic termini to release them from the inner surface of plasma membrane, subsequently leading to the decreased ENaC open probability (top right). Aldosterone elevates the concentration of PIP3 by activating of phosphotidylinositol-3-kinas (PI 3-K). PIP3 stimulates ENaC activity by further "locking" of the cytoplasmic termini to the inner surface of plasma membrane because of one more negative charges (middle right). In the absence of aldosterone, the inner leaflet of the plasma membrane contains PIP2 rather than PIP3 (bottom left). In the presence of aldosterone, PIP3 is produced and somehow stimulates ENaC surface expression. Illustration by Josh Gramling—Gramling Medical Illustration.
It has also been shown that PIP3 in the cells can be selectivelylabeled by a specific green fluorescent protein–fused,GRP1-PH domain. Using this method, recent studies have shownthat there is an obvious elevation of apical membrane PIP3 inresponse to insulin (43). We recently demonstrated that bothPIP3 and the N-terminal tail of -ENaC are required for aldosterone-inducedENaC activity and trafficking (62). However, whether PIP3 interactswith the N-terminal tail of -ENaC remains to be determined.For this model to work, PIP3 would need to be >10-fold moreeffective than PIP2 because PIP3 concentration, even after stimulation,is only approximately 10% of PIP2 (24,25). Therefore, we suggestthat the N-terminal tail of -ENaC contains a specific PIP3 bindingmotif. We hypothesize a working model that aldosterone-inducedsynthesis of PIP3 seems to be important both for acutely elevatingENaC open probability (Figure 3, top) and for increasing ENaCcell surface expression (Figure 3, bottom).
The purpose of this review is to provide a new explanation forthe regulation of ENaC by purinergic and corticoid receptors.In particular, the concept of interaction of cytoplasmic domainsof ENaC with anionic phospholipids suggests a novel mechanismby which ENaC could be regulated by the lipid composition ofthe inner leaflet of the plasma membrane.
Acknowledgments
H.-P.M. was supported by the Department of Health and HumanServices, National Institutes of Health (NIH) Grant 1R01-DK067110,and D.C.E. was supported by NIH Grant R37-DK37963 and P01-DK61521.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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S. S.P. Wildman, J. Marks, C. M. Turner, L. Yew-Booth, C. M. Peppiatt-Wildman, B. F. King, D. G. Shirley, W. Wang, and R. J. Unwin Sodium-Dependent Regulation of Renal Amiloride-Sensitive Currents by Apical P2 Receptors
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[Abstract][Full Text][PDF]
V. Vallon P2 receptors in the regulation of renal transport mechanisms
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[Abstract][Full Text][PDF]
K. M. Weixel, R. S. Edinger, L. Kester, C. J. Guerriero, H. Wang, L. Fang, T. R. Kleyman, P. A. Welling, O. A. Weisz, and J. P. Johnson Phosphatidylinositol 4-Phosphate 5-Kinase Reduces Cell Surface Expression of the Epithelial Sodium Channel (ENaC) in Cultured Collecting Duct Cells
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A. Bengrine, J. Li, L. L. Hamm, and M. S. Awayda Indirect Activation of the Epithelial Na+ Channel by Trypsin
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L. M. Satlin, M. D. Carattino, W. Liu, and T. R. Kleyman Regulation of cation transport in the distal nephron by mechanical forces
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M. N. Helms, L. Liu, Y.-Y. Liang, O. Al-Khalili, A. Vandewalle, S. Saxena, D. C. Eaton, and H.-P. Ma Phosphatidylinositol 3,4,5-Trisphosphate Mediates Aldosterone Stimulation of Epithelial Sodium Channel (ENaC) and Interacts with {gamma}-ENaC
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[Abstract][Full Text][PDF]
D. G. Warnock and B. C. Rossier Renal Sodium Handling: The Role of the Epithelial Sodium Channel
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[Full Text][PDF]
- and 
-ENaC with the negatively charged membrane phospholipids. The exact nature of this interaction will require further investigation. 
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