The function and regulation of acid‐sensing ion channels (ASICs) and the epithelial Na⁺ channel (ENaC): IUPHAR Review 19

Abstract

*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...

Composition and Control of a Deg/ENaC Channel during Presynaptic Homeostatic Plasticity

“…But, given that ENaC channels have potent activities to control cellular physiology in tissues as diverse as the kidney, lung and colonic epithelium, it seems likely that we are only scratching the surface with respect to ENaC and ASIC channel function in the nervous system. Furthermore, even in those systems where ENaC channels are a focus of significant research, there remains much to learn about the regulatory mechanisms that control channel expression, trafficking and surface retention (Boscardin et al, 2016). …”

Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

“…ASICs are chordate-specific members of the degenerin/epithelial sodium channel family that are widely distributed in the nervous system and many non-neuronal cells (Boscardin et al, 2016). They are primary mammalian acid sensors and as such are activated by protonation (Waldmann et al, 1997).…”

Acid sensing ion channel 2: A new potential player in the pathophysiology of multiple sclerosis

“…Our interest in this class of genes, and in particular on ASIC2, was further motivated by literature evidence showing that ASIC channels are involved in multiple biological functions such as: pain modulation, mechanosensation, acidosis‐induced neuronal death and neurotransmission (Kang et al., ; Kweon & Suh, ; Ortega‐Ramírez et al., ; Sherwood, Lee, Gormley, & Askwith, ; Wemmie, Taugher, & Kreple, ). ASICs are activated in response to extracellular acidification occurring in neurotransmission at synaptic level (reviewed in Boscardin, Alijevic, Hummler, Frateschi, & Kellenberger, ). Most recently, ASICs have been involved in regulating synaptic plasticity in the amygdala (Du et al., ) and the generation of postsynaptic currents by ASIC1a and ASIC2 was reported to act on the reduction of cocaine addiction (Kreple et al., ).…”