Acid-Sensing (Proton-gated) Ion Channels (ASICs) and Epithelial Sodium Channels (ENaCs)

The recently discovered ENaC/degenerin gene family encodes sodium channels involved in various cell functions in metazoans. The subfamilies include the degenerins, which are part of a mechanosensory complex in the nematode C. elegans, the FMRFamide peptide-gated sodium channel FaNaC present in snails, and the mammalian subfamilies ENaC and ASICs. This entry focuses on the mammalian channels.

Structurally, functional ENaC and ASICs are composed of several homologous subunits that are arranged around the central channel pore. Analysis of the functional ENaC or FaNaC complex suggests that they form tetramers. ENaC has a fixed subunit stoichiometry with two a and one each of β and γ subunits. ASICs can form hetero- and homomultimeric channels. ENaC subunits have a predicted mass of 73 - 76 kDa; ASIC subunits are somewhat smaller with 58 - 63 kDa. ENaC and ASIC subunits have intracellular N- and C-termini, two transmembrane domains and a large extracellular loop. This topology has been experimentally verified for α ENaC and for ASIC2a. Structure-function studies in ENaC identified the region immediately preceding the second transmembrane domain as important for ion permeation and selectivity and for binding of the pore blocker amiloride.

ENaC is highly selective for Na+ over K+ (pNa/pK ≥ 100), while ASICs are less selective, with a pNa/pK ratio of ~10. ENaC and ASICs do not conduct divalent cations except for ASIC1a that has a low but significant permeability to Ca2+ that may be physiologically important. All members of the ENaC/degenerin family are inhibited by amiloride, which acts as a pore blocker. The IC50 for current block on cloned ENaC and ASICs is 0.1 mM and 10-100 mM respectively for amiloride, and 0.01 mM and ~10 mM for the amiloride derivative benzamil. ENaC is a constitutively active channel. ASICs are normally closed channels that are transiently activated by extracellular acidification and subsequently inactivate in the continued presence of the extracellular acidic stimulus. The mechanism of pH-gating of ASICs is currently not known. For ASIC3 it has been suggested that acidification removes a tonic channel block by extracellular Ca2+.

ENaC is expressed at the apical membrane of epithelia, where it mediates transepithelial Na+ transport in a two-step process that involves entry of Na+ via ENaC and extrusion of the intracellular Na+ by the basolaterally located Na+/K+-ATPase. In the kidney and the colon, the transepithelial Na+ transport is crucial for Na+ and K+ homeostasis and for the control of blood pressure. In the lung or in salivary glands, Na+ transport is important for keeping the composition and the volume of the luminal fluid constant. ENaC in the taste buds of the tongue is involved in salt taste sensation. ENaC function in the kidney, the colon and the taste buds is regulated by aldosterone. Mice that are deficient of either ENaC subunit die soon after birth, either from respiratory or metabolic problems. Liddle syndrome, a rare form of hypertension, is caused by hyperactivating ENaC mutations, while pseudohypoaldosteronism type 1, which is accompanied by renal salt loss and hypotension, is caused by loss-of-function ENaC mutations.

ASICs are widely distributed in the central and the peripheral nervous system, where they are thought to induce neuronal depolarization and action potential generation in response to extracellular acidification. Mice that are deficient of one or several ASIC genes are apparently healthy. Experiments that compared wild type mice with those deficient of certain ASIC genes indicate potential roles of ASICs in learning, fear conditioning, neurodegeneration after ischemia and in pain sensation.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Subfamily ENaC ASIC
Types/Subtypes ENaC is composed of three homologous subunits,  α, β, γ Four genes and splice variants of subunits (ASIC1-4). Functional ASIC channels are heteromeric or homomultimeric assemblies of subunits
Alternative Nomenclature Amiloride-sensitive Na channel
Gene names/data base entry names: SCNN1A/SCAA, (αENaC);
SCNN1B/SCAB, (βENaC); SCNN1G/SCAG, (γENaC)
BNaC2, ACCN2 (= ASIC1a); ASICβ (= ASIC1b); BNaC1, BNC1, MDEG, MDEG1, ACCN1 (= ASIC2a); MDEG2 (= ASIC2b); DRASIC, hTNaC1 (= ASIC3); SPASIC (= ASIC4)
Structural Information Subunit contains two transmembrane domains
Functional channel is a tetramer
α 669 aa; β 640 aa; γ 649 aa (all human)
ASIC1a, 528 aa (human); ASIC1b, 559 aa (rat); ASIC2a, 512 aa (human); ASIC2b, 563 aa (rat); ASIC3, 531 aa (human); ASIC4 539 aa (human)
Tissue Expression Kidney, colon, salivary glands, airway epithelia, skin, taste buds Central and peripheral nervous system
Conductance (Na+) 4-5 pS 10-15 pS
Ionic Selectivity Li+ > Na+ >>>K+ Li+ = Na+ > K+
Control of Channel Activity Constitutively active channel Activated by extracellular pH drop
Blockers Amiloride (A7410)
Benzamil (B2417)
Triamteren
Amiloride (A7410)
Benzamil (B2417)
NSAIDs (e.g. salicylic acid; S5922)
Acetylsalicylic acid (A2093, A5376)
Flurbiprofen (F8514)
Ibuprofen (I4883, I7905, I1892)
Diclofenac (D6899)
Gd3+
Psalmotoxin 1 (ASIC1a)
The sea anemone peptide toxin APETx3 (ASIC3)
Modulators Proteases (e.g. trypsin; T1426)
Aldosterone (A9477) (induces cell surface expression)
FMRFamide (P4898) and related peptides proteases (trypsin (T1426), chymotrypsin (C4129), proteinase K (P6556)) Ca2+, Mg2+, Zn2+  
Physiological Function Na+ homeostasis, blood pressure regulation, regulation of airway surface liquid level, taste sensation Possibly involved in pain sensation, memory functions, fear conditioning, neurodegeneration after ischemia/hypoxia
Disease Relevance Hypertension, Liddle syndrome, pseudohypoaldosteronism type 1 Not Known

 

Abbreviations

NSAIDs: Nonsteroidal anti-inflammatory drugs
APETx3: Anthopleura elegantissima toxin 3

 

Similar Products


     

References