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TOPICAL REVIEW |
1 University of Texas Health Science Center at San Antonio, Department of Physiology, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
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Abstract |
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- and 
-ENaC subunits and the latter with cytosolic regions immediately following the second transmembrane domains in these two subunits. PI(4,5)P2 binding to ENaC appears saturated at rest and necessary for channel gating. Thus, decreases in cellular PI(4,5)P2 levels may serve as a convergence point for inhibitory regulation of ENaC by G-protein coupled receptors and receptor tyrosine kinases. In contrast, apparent PI(3,4,5)P3 binding to ENaC is not saturated. This enables the channel to respond with gating changes in a rapid and dynamic manner to signalling input that influences cellular PI(3,4,5)P3 levels.
(Received 22 December 2006;
accepted after revision 22 January 2007;
first published online 1 February 2007)
Corresponding author J. D. Stockand: University of Texas Health Science Center, Department of Physiology, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Email: stockand{at}uthscsa.edu
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Introduction |
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TopAbstractIntroductionReferences |
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Channels responsive to phosphatidylinositides are diverse ranging from those highly selective for Ca2+ (e.g. Cav2 channels; Wu et al. 2002; Gamper et al. 2004), Na+ (e.g. ENaC; Tong et al. 2004; Ma et al. 2002), K+ (e.g. Kv7, Kir6, TWIK channels; Hilgemann & Ball, 1996; Huang et al. 1998; Zhang et al. 1999; Suh & Hille, 2002; Dong et al. 2002; Bian et al. 2004; Lopes et al. 2005) and Cl– (e.g. CFTR; Himmel & Nagel, 2004) to ones selective for cations in general (e.g. CNG and TRP channels; Chuang et al. 2001; Prescott & Julius, 2003). Additional diversity is apparent when considering that these channels are comprised of subunits having very different tertiary structures ranging from those containing only two transmembrane domains to those with six or more. Phosphatidylinositide-sensitive channels, moreover, range from being ligand- to voltage-gated, localized to sensory neurons and epithelial cells, as well as being rectifying and non-rectifying. Despite this apparent diversity, common themes regarding phosphoinositide binding sites and mechanism of regulation are beginning to emerge. Phosphatidylinositides, including PI(4,5)P2 and PI(3,4,5)P3, directly interact with channel subunits at specific sites to modulate gating.
Recent studies are consistent with ENaC being a channel that binds phosphatidylinositides and is sensitive to direct regulation by these signalling molecules (Pochynyuk et al. 2006). ENaC is a Na+-selective, non-voltage gated, non-inactivating ion channel in the ENaC/Deg superfamily (Kellenberger & Schild, 2002; Garty & Palmer, 1997; Alvarez et al. 2000; Benos & Stanton, 1999). ENaC is a heteromeric channel comprised of three similar but distinct subunits: 
, and (Canessa et al. 1993, 1994; McNicholas & Canessa, 1997; Fyfe & Canessa, 1998; Fyfe et al. 1998). ENaC subunits share a common tertiary structure having comparatively short amino- and carboxy-terminal cytosolic domains (
50–100 amino acids) separated by two trans-membrane domains and a large (450 amino acids) extracellular domain. All three ENaC subunits contribute to the functional channel and are required for maximal activity (Canessa et al. 1993, 1994; McNicholas & Canessa, 1997; Fyfe & Canessa, 1998; Fyfe et al. 1998).
ENaC is localized to the luminal plasma membrane of Na+-(re)absorbing epithelia, such as that lining the distal renal nephron and colon, and lungs (Garty & Palmer, 1997; Eaton et al. 2004). ENaC is a final effector of corticoid steroids, including glucocorticoids in the lungs and mineralocorticoids, as the end product of the renin–angiotensin–aldosterone cascade, in the kidney (Verrey, 1998; Stockand, 2002). Activity of this channel is limiting for Na+ transport across these epithelial tissues with corticosteroids increasing ENaC activity. Consequently, ENaC plays a critical role in the local movement of electrolytes and water across epithelial barriers, as well as control of total body electrolyte and water homeostasis. This function places ENaC as a central effector modulating blood pressure and epithelia surface hydration. Thus, dysfunction and aberrant regulation of this channel leads to a spectrum of diseases ranging from hyper- and hypo-tension associated with improper renal Na+ conservation and wasting, respectively, to respiratory syndromes linked to overly wet lungs and dry airways (Hummler & Horisberger, 1999; Bonny & Hummler, 2000; Lifton et al. 2001; Rossier et al. 2002; Mall et al. 2004).
Regulation of ENaC by phosphatidylinositides
The first indication that ENaC could be directly regulated by phosphatidylinositides was provided by Ma and colleagues (Ma et al. 2002). This group demonstrated that decay in ENaC activity in plasma membrane patches excised from renal epithelial cells was tightly linked to PI(4,5)P2 metabolism. Addition of PI(4,5)P2 to the intracellular face of ENaC in these excised patches countered spontaneous decreases in channel activity, whereas scavenging and hydrolysis of PI(4,5)P2 accelerated decreases in channel activity. The primary effect of PI(4,5)P2 on ENaC was not related to control of membrane levels of the channel but rather appeared to be an effect on gating. That manipulation of PI(4,5)P2 levels correlated with changes in ENaC activity in excised patches suggested tight spatial coupling between the final effector of this phosphoinositide and the channel.
Several different laboratories have now reconfirmed the relation between changes in membrane PI(4,5)P2 levels and ENaC activity (Yue et al. 2002; Kunzelmann et al. 2005; Tong & Stockand, 2005). Moreover, mounting evidence supports the idea that decreasing membrane PI(4,5)P2 levels serves as an important mechanism through which G-protein coupled receptors (GPCR) and receptor tyrosine kinases (RTK) modulate ENaC activity. For instance, signalling in response to activation of purinergic receptors and other Gq/11-coupled receptors inhibits Na+ absorption and ENaC activity in tracheal and collecting duct epithelial cells and in expression studies (Ma et al. 2002; Kunzelmann et al. 2005; Tong & Stockand, 2005). Gq/11-coupled receptors decrease PI(4,5)P2 levels via activating PLC-. Scavenging PI(4,5)P2 abolishes purinergic regulation of ENaC (Kunzelmann et al. 2005). Inhibition of PI4-K and DAG kinase, two kinases involved in regeneration of PI(4,5)P2, moreover, slows recovery of ENaC activity from purinergic inhibition in a manner similar to that reported for blockade of PI4-K on recovery of KCNQ activity in response to muscarinic signalling (Kunzelmann et al. 2005). Muscarinic signalling is thought to decrease activity of this latter phosphoinositide-sensitive channel by promoting PI(4,5)P2 metabolism (Suh & Hille, 2002).
Activation of receptor tyrosine kinases, such as the epidermal growth factor (EGF) receptor, which are capable of decreasing PI(4,5)P2 levels via PLC-, also decrease ENaC activity. Buffering PI(4,5)P2 to prevent dynamic changes in its levels, uncouples ENaC from inhibition by activation of the EGF receptor implicating this second messenger as the causative agent in changing channel activity (Tong & Stockand, 2005).
Irrespective of how PI(4,5)P2 is manipulated, be it through physiological signalling via membrane receptors or through pharmacological and genetic tools, decreases in the levels of this phosphatidylinositide lead to corresponding decreases in ENaC activity and open probability (Ma et al. 2002; Yue et al. 2002; Tong & Stockand, 2005). Thus, inhibition of ENaC in response to receptor-linked PTKs (RTKs) and Gq/11-coupled receptor signalling has many parallels with regulation of TRP, GIRK, KCNQ and P/Q- and N-type Ca2+ channels by these receptors (Kobrinsky et al. 2000; Chuang et al. 2001; Wu et al. 2002; Prescott & Julius, 2003; Gamper et al. 2004; Li et al. 2005). The generalized conclusion for these other phosphoinositide-sensitive channels is that decreases in PI(4,5)P2 levels in response to RTK and GPCR signalling lead to dissociation of the phosphoinositide from the channel decreasing channel activity.
ENaC gating is also sensitive to the cellular levels of the phosphoinositide products of PI3-K, primary of which is PI(3,4,5)P3 (Ma et al. 2002; Tong et al. 2004; Staruschenko et al. 2004b; Pochynyuk et al. 2005). Direct regulation of ENaC open probability by PI(3,4,5)P3 was first proposed following experiments in a mammalian expression system where changes in channel activity were noted to closely follow changes in the active state of PI3-K and membrane levels of PI(3,4,5)P3 (Tong et al. 2004). In addition, the open probability of ENaC in excised patches increased upon relief of PI3-K from inhibition and in response to addition of exogenous PI(3,4,5)P3. The observation of tight spatiotemporal coupling between changing PI(3,4,5)P3 levels and ENaC activity combined with the observations that PI(3,4,5)P3 affected channel gating and activated the channel in excised patches led to the hypothesis that ENaC or a protein closely associated with the channel contains a functional PI(3,4,5)P3 binding site. With regard to this hypothesis, physical occupancy of this binding site then would affect gating. Testing of this hypothesis has resulted in identification of a putative PI(3,4,5)P3 binding site within the channel that impinges upon ENaC gating for mutation of residues within this site abrogate PI3-K and PI(3,4,5)P3 regulation (Pochynyuk et al. 2005).
The physiological importance of direct regulation of ENaC by PI(3,4,5)P3 signalling in collecting duct principal cells responsible for fine-tuning plasma volume and electrolyte content is exemplified by results such as those shown in Fig. 1. Shown in Fig. 1A are current traces of ENaC before and after inhibition of PI3-K in a cell-attached patch made on the apical membrane of a principal cell in a collecting duct freshly isolated from a rat maintained with a low Na+ diet. In principal cells from such salt-restricted animals, ENaC is active having a high open probability (Palmer & Frindt, 1986; Frindt et al. 1990; Sun et al. 2006). As is clear, ENaC open probability rapidly decreases soon after inhibiting PI3-K. This decrease in channel activity parallels decreases in apical membrane PI(3,4,5)P3 levels following PI3-K inhibition as shown in Fig. 1B. In combination with the emerging understanding of the possible direct effects of PI(3,4,5)P3 on ENaC gating established in heterologous expression systems, the rapidity of simultaneous decreases in ENaC open probability and apical PI(3,4,5)P3 levels argue that this mechanism plays a role in setting the activity of this channel in native principal cells.
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Putative PI(3,4,5)P3 and PI(4,5)P2 binding sites within ENaC
Several studies have begun probing putative phosphatidylinositide binding sites within ENaC. However, this area of investigation is just emerging and true understanding of whether ENaC, and for that matter any other phospohoinositide-senstive channel, contains a bona fide binding site and the locale and structures of potential phosphoinositide binding sites within ion channels is currently lacking. Studies investigating putative binding sites within ENaC and other phosphoinositide-sensitive channels most often do so by combining functional electrophysiology measurements of channel activity with mutagenesis. A limitation to using this approach is that it is indirect in its ability to identify actual binding sites. This stands in contrast to some currently available biochemical and structural chemistry approaches that have yet to be applied to this area of investigation.
Two studies point to the cytosolic portion of the amino-terminus of -ENaC as being important for PI(4,5)P2 regulation (Yue et al. 2002; Kunzelmann et al. 2005). Mutation of this site in ENaC does not affect surface expression of the channel but does decrease resting channel activity and open probability in a manner similar to depleting PI(4,5)P2. While not definitive, one interpretation of these observations is that this portion of the channel contains a binding site that is occupied by saturating concentrations of PI(4,5)P2 at rest with occupancy being necessary/permissive for normal channel gating. It also remains to be determined whether this area of ENaC encompasses a partial or complete binding site, though biochemical results demonstrate it is necessary for PI(4,5)P2 to interact with the channel (Yue et al. 2002).
Our laboratory recently implicated the cytosolic region just following the second transmembrane domain in -ENaC as contributing to a PI(3,4,5)P3 binding site functionally linked to control of channel gating (Booth et al. 2003; Tong et al. 2004; Pochynyuk et al. 2005). However, this investigation was also constrained by the limitations noted above. Similar to the amino-terminus of the -ENaC subunit implicated in PI(4,5)P2 binding, this region contains several well-conserved positive-charged residues. As demonstrated by the results in Fig. 2, which are re-produced from an earlier study, deletion of these residues disrupts the ability of ENaC to physically interact with PI(3,4,5)P3 (Pochynyuk et al. 2005). While our biochemical and electrophysiology studies are consistent with direct interactions between the phosphoinositide and channel, additional study is required prior to fully recognizing this site as a bona fide binding site. Moreover, it is not yet clear whether this domain encompasses a complete or partial binding site.
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Results in Fig. 3 typify mutagenesis scans of ENaC subunits attempting to identify potential PI(4,5)P2 and PI(3,4,5)P3 binding sites. Cytosolic regions just following the second transmembrane domains in - and - but not -ENaC contribute to regulation by PI(3,4,5)P3 but not PI(4,5)P2, whereas the cytosolic domains in the amino-termini of - and -ENaC contribute to PI(4,5)P2 but not PI(3,4,5)P3 regulation. One interpretation of these functional results is that ENaC contains distinct regions important to PI(4,5)P2 and PI(3,4,5)P3 regulation. While still early in our understanding, extrapolation of these observations suggests that binding sites within - and -ENaC subunits bestow phosphatidylinositide sensitivity to the channel.
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It is not clear yet what provides selectivity to phosphoinositide binding sites within ion channels; however, alanine substitution of the conserved negative-charged and bulky residues within the putative PI(3,4,5)P3 binding site in -ENaC enhances basal activity and responses to PI3-K signalling (Pochynyuk et al. 2005). These findings suggest that these residues, in addition to the conserved positive-charged residues, may influence binding affinity and selectivity. Non-charged and negative-charged residues in the putative binding sites of other phosphatidylinositide-sensitive channels are thought to play a similar role (Zhang et al. 1999; Rohacs et al. 2003).
Functional implications of phosphatidylinositide regulation of EnaC
It is now clear that ENaC is a phosphatidylinositide-sensitive channel responding to both PI(4,5)P2 and PI(3,4,5)P3. The former phosphoinositide is necessary for normal channel gating and may serve as a focal point for convergence of inhibitory signalling from GPCR and RTK. The nature of ENaC modulation by PI(4,5)P2 appears to be amenable to both acute and chronic forms of channel regulation for ENaC activity does not spontaneously recover from PI(4,5)P2 depletion but rather requires re-synthesis of this phosphatidylinositide. In contrast, PI(3,4,5)P3 signalling has the potential to acutely increase the activity of ENaC. The close spatiotemporal coupling between changes in ENaC gating and PI(3,4,5)P3 levels would allow the channel to respond precisely in a dynamic and rapid manner to ever-changing local and systemic cues modulating Na+ movement across epithelial barriers.
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573Q-600P and 