Functional cross talk between ENaC and pendrin - Semantic Scholar

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Sep 12, 2007 - crystal structure of ASIC1 showing that it is a homotrimer. As ENaC and ASIC are both members of the degenerin family of channels with.
Am J Physiol Renal Physiol 293: F1439–F1440, 2007; doi:10.1152/ajprenal.00402.2007.

Editorial Focus

Functional cross talk between ENaC and pendrin Rebecca P. Hughey and Thomas R. Kleyman Department of Medicine, Renal-Electrolyte Division, and Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Submitted 29 August 2007; accepted in final form 12 September 2007 ⫹

CHANNELS (ENaC) are expressed in the aldosterone-sensitive distal nephron, where they serve as the final site of renal Na⫹ reabsorption and participate in the regulation of extracellular fluid volume and blood pressure. ENaC gain-offunction mutations are associated with hypertension, whereas loss-of-function mutations are associated with hypotension. Appreciation of the features that regulate ENaC expression and activity contributes to our understanding of the role of the kidney in the regulation of blood pressure. ENaC structure, assembly, and maturation. ENaC is assembled into a presumed trimeric structure (␣1␤1␥1) from three highly homologous subunits within the endoplasmic reticulum (ER), although higher ordered stoichiometries have also been proposed (3, 12, 21). The assembly appears to be inefficient given that only a limited fraction of newly synthesized subunits are eventually found in channels that reach the cell surface (16, 26). Each subunit exhibits intracellular NH2 and COOH termini, two transmembrane domains, and a large extracellular loop (ECL) with numerous sites for N-linked glycosylation (2, 3). Immature channels that exit the ER are subsequently processed by remodeling of the N-linked glycans and proteolytic cleavage of the ECLs (5, 6). Data published in recent years clearly indicate that ENaC is activated by proteolytic release of small inhibitory peptides from the ␣- and ␥-subunits (1, 4). Noncleaved ENaCs exhibit a low open probability (Po). The trans-Golgi network (TGN)localized protease furin cleaves ␥ at one site but ␣ at two sites, releasing a 26-mer inhibitory peptide from ␣ and producing a channel with moderate Po (4). Subsequent cleavage of ENaC by prostasin releases an additional 43-mer peptide from the ␥-subunit, producing a channel with a very high Po (1). Interestingly, ENaCs with mutated cleavage sites and lacking the inhibitory sequences are active, indicating that release of the inhibitory peptides rather than cleavage per se activates the channel (1, 4). This conclusion is supported by a finding that endogenous ENaCs in cortical collecting duct cells and human airway cells, as well as mouse ENaC expressed in Xenopus ooctyes, are inhibited by synthetic versions of the ␣ 26-mer and ␥ 43-mer peptides (1, 4). Noncleaved channels are also present on the cell surface and can be activated by exogenous proteases, providing a putative reserve of ENaC that can be rapidly activated (7). In whole-animal studies of renal ENaC regulation by hormones, drugs, toxic compounds, or pathological conditions, a shift from an 85-kDa form of ␥ to a 70-kDa form of ␥ has consistently been associated with states of increased ENaC activity (8, 9, 15, 19, 22). The 70-kDa form likely results from EPITHELIAL Na

Address for reprint requests and other correspondence: R. P. Hughey, Univ. of Pittsburgh School of Medicine, S933 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261 (e-mail: [email protected]). http://www.ajprenal.org

proteolytic processing of the full-length 85-kDa form by one or multiple cleavage events. Pendrin regulation of ENaC expression and activity. Kim et al. (10) now report that Slc26a4 null mice lacking the Cl⫺/HCO⫺ 3 exchanger pendrin exhibited a blunted increase in blood pressure and renal ENaC activity and subunit levels, in response to either dietary sodium restriction or aldosterone administration. No changes were noted in 1) other renal epithelial Na⫹ transporters, 2) levels of ENaC subunits in colon and thyroid, and 3) circulating levels of renal, adrenal, and thryroid hormones, as well as vasopressin action (10). Altogether, their findings are consistent with a renal-specific pendrin-mediated regulation of ENaC expression and activity. Pendrin and ENaC are both localized in the aldosteronesensitive segment of the renal nephron. However, they reside in different cell types that do not communicate through gap junctions (10, 13). As increases in levels of expression of ␣-, ␤-, and ␥-ENaC were blunted in response to aldosterone in Slc26a4 null mice compared with normal mice (10), the regulation of ENaC subunit transcription may be compromised by local alterations in ion transport in the absence of pendrin. The mechanism for this type of regulation is unknown. The authors also noted that the “cleaved and activated” 70-kDa form of ␥-ENaC was preferentially reduced in Slc26a4 null mice compared with normal mice treated with aldosterone (10). This observation suggests that pendrin also regulates ENaC by reducing the fraction of the channel activated by proteases. A reduced fraction of “cleaved and activated” ENaC could result from 1) an increase in the degradation of subunits and/or a decrease in the assembly of ␣␤␥-ENaC within the ER, 2) a decrease in the fraction of ENaC processed while traversing the Golgi complex and TGN (compared with the pool that seemingly bypasses this step), 3) a decrease in the levels of channel-activating-proteases (CAPs, such as prostasin) or a decrease in the residence time for the channel on the cell surface, or 4) changes in the ratio of protease and protease inhibitor at the cell surface (11, 14, 17, 20, 23, 24). As Kim et al. (10) observed normal redistribution of ENaC from cytoplasmic vesicles to the apical plasma membrane of principal cells in the null mice after aldosterone infusion, the mostly likely site of pendrin-dependent regulation of ENaC maturation may very well be in a postbiosynthetic compartment and involve proteases or protease inhibitors present in the tubule lumen. Loss-of-function mutations in the human Slc26a4 gene are associated with deafness, and new data indicate that Slc26a4 knockout in mice causes both deafness and acidification of the vestibular lumen (18, 25). Thus the question now arises: Do pendrin-dependent alterations in renal tubule luminal pH affect the activity and/or levels of expression of proteases that cleave and activate ENaC?

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Editorial Focus F1440 NOTE ADDED IN PROOF

Jasti et al. Nature 449: 316 –323, 2007) recently published the crystal structure of ASIC1 showing that it is a homotrimer. As ENaC and ASIC are both members of the degenerin family of channels with high amino acid homology, ENaC may also be an ␣1␤1␥1 heterotrimer. GRANTS This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-065161. REFERENCES 1. Bruns JB, Carattino MD, Sheng S, Maarouf AB, Weisz OA, Pilewski JM, Hughey RP, Kleyman TR. Epithelial Na⫹ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma subunit. J Biol Chem 282: 6153– 6160, 2007. 2. Canessa CM, Meriallat AM, Rossier BC. Membrane topology of the epithelial sodium channel in intact cells. Am J Physiol Cell Physiol 267: C1682–C1690, 1994. 3. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC. Amiloride-sensitive epithelial Na⫹ channel is made of three homologous subunits. Nature 367: 463– 467, 1994. 4. Carattino MD, Sheng S, Bruns JB, Pilewski JM, Hughey RP, Kleyman TR. The epithelial Na⫹ channel is inhibited by a peptide derived from proteolytic processing of its alpha subunit. J Biol Chem 281: 18901–18907, 2006. 5. Hughey RP, Mueller GM, Bruns JB, Kinlough CL, Poland PA, Harkleroad KL, Carattino MD, Kleyman TR. Maturation of the epithelial Na⫹ channel involves proteolytic processing of the ␣- and ␥-subunits. J Biol Chem 278: 37073–37082, 2003. 6. Hughey RP, Bruns JB, Kinlough CL, Harkleroad KL, Tong Q, Carattino MD, Johnson JP, Stockand JD, Kleyman TR. Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem 279: 18111–18114, 2004. 7. Hughey RP, Bruns JB, Kinlough CL, Kleyman TR. Distinct pools of epithelial sodium channels are expressed at the plasma membrane. J Biol Chem 279: 48491– 48494, 2004. 8. Kim SW, de Seigneux S, Sassen MC, Lee J, Kim J, Knepper MA, Frøkiær J, Nielsen S. Increased apical targeting of renal ENaC subunits and decreased expression of 11␤HSD2 in HgCl2-induced nephrotic syndrome in rats. Am J Physiol Renal Physiol 290: F674 –F687, 2006. 9. Kim SW, Wang W, Sassen MC, Choi KC, Han JS, Knepper MA, Jonassen TE, Frøkiær J, Nielsen S. Biphasic changes of epithelial sodium channel abundance and trafficking in common bile duct ligationinduced liver cirrhosis. Kidney Int 69: 89 –98, 2006. 10. Kim YH, Pech V, Spencer KB, Beierwaltes WH, Everett LA, Green ED, Shin W, Verlander JW, Sutliff RL, Wall SM. Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice. Am J Physiol Renal Physiol 293: F1314 –F1324, 2007. 11. Knight KK, Olson DR, Zhou R, Snyder PM. Liddle’s syndrome mutations increase Na⫹ transport through dual effects on epithelial Na⫹ channel surface expression and proteolytic cleavage. Proc Natl Acad Sci U S A 103: 2805–2808, 2006.

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