*These authors contributed equally.Acid-sensing ion channels (ASICs) and the epithelial Na + channel (ENaC) are both members of the ENaC/degenerin family of amiloride-sensitive Na + channels. ASICs act as proton sensors in the nervous system where they contribute, besides other roles, to fear behaviour, learning and pain sensation. ENaC mediates Na + reabsorption across epithelia of the distal kidney and colon and of the airways. ENaC is a clinically used drug target in the context of hypertension and cystic fibrosis, while ASIC is an interesting potential target. Following a brief introduction, here we will review selected aspects of ASIC and ENaC function. We discuss the origin and nature of pH changes in the brain and the involvement of ASICs in synaptic signalling. We expose how in the peripheral nervous system, ASICs cover together with other ion channels a wide pH range as proton sensors. We introduce the mechanisms of aldosterone-dependent ENaC regulation and the evidence for an aldosterone-independent control of ENaC activity, such as regulation by dietary K + . We then provide an overview of the regulation of ENaC by proteases, a topic of increasing interest over the past few years. In spite of the profound differences in the physiological and pathological roles of ASICs and ENaC, these channels share many basic functional and structural properties. It is likely that further research will identify physiological contexts in which ASICs and ENaC have similar or overlapping roles. AbbreviationsAQP, aquaporin; ASDN, aldosterone-sensitive distal nephron; ASIC, acid-sensing ion channel; BASIC, bile acid-activated ion channel; BK, big calcium-activated K + channel; CA, carbonic anhydrase; CAP-1, -2, or-3, channel activating proteases; Ca v , voltage-gated Ca2 + channel; CCD, cortical collecting duct; CD, collecting duct; PHA-1, pseudohypoaldosteronism type 1; CFTR, cystic fibrosis transmembrane conductance regulator; CNT, connecting tubule; CF, cystic fibrosis; CLCN/Kb, voltage-sensitive chloride channel Kb; DCT, distal convoluted tubule; DRG, dorsal root ganglion; ENaC, amiloride-sensitive epithelial sodium channel; EPSP, excitatory post-synaptic potential; FaNaC, FMRFa-activated Na + channel; FMRFa, PheMet-Arg-Phe-amide; GMQ, 2-guanidine-4-methylquinazoline; GPI, glycosylphosphatidyl-inositol; HAI, hepatocyte growth factor activator inhibitor; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; I A , A-type current of rapid inactivating K + channels; iGluR, ionotropic glutamate receptor; I K , K + current; I Na , Na + current; I h , current produced by HCN channels; I max , maximal current amplitude; Kir, inward rectifier K + channel; K v , voltage-gated K + channel; MR, mineralocorticoid receptor; Na v , voltage-gated Na + channel; NBC, Na + , -HCO 3 -cotransporter; NCC, Na +-Cl À cotransporter; NHE, Na +-H + exchanger; OSR1/SPAK, Ste20-related protein kinases; P2X, purinergic receptor; PcTx1, Psalmotoxin 1; pH 50 , pH of half-maximal activation; pHe, extracellular pH; pH 50 Inh./Act., pH of h...

Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal lifethreatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na + /Cl 2 cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific aENaC-knockout mice (Scnn1a) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype.

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The amiloride-sensitive epithelial sodium channel (ENaC) and the thiazide-sensitive sodium chloride cotransporter (NCC) are key regulators of sodium and potassium and colocalize in the late distal convoluted tubule of the kidney. Loss of the ENaC subunit leads to a perinatal lethal phenotype characterized by sodium loss and hyperkalemia resembling the human syndrome pseudohypoaldosteronism type 1 (PHA-I). In adulthood, inducible nephron-specific deletion ofENaC in mice mimics the lethal phenotype observed in neonates, and as in humans, this phenotype is prevented by a high sodium (HNa)/low potassium (LK) rescue diet. Rescue reflects activation of NCC, which is suppressed at baseline by elevated plasma potassium concentration. In this study, we investigated the role of the ENaC subunit in the PHA-I phenotype. Nephron-specificENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking ENaC orΕΝaC, an HNa/LK diet did not normalize plasma potassium (K) concentration or increase NCC activation. However, when K was eliminated from the diet at the time that ENaC was deleted, plasma K concentration and NCC activity remained normal, and progressive weight loss was prevented. Loss of the late distal convoluted tubule, as well as overall reduced ENaC subunit expression, may be responsible for the more severe hyperkalemia. We conclude that plasma K concentration becomes the determining and limiting factor in regulating NCC activity, regardless of Na balance in ENaC-deficient mice.