Alveolar nonselective channels are ASIC1a/α-ENaC channels and contribute to AFC

Abstract

A thin fluid layer in alveoli is normal and results from a balance of fluid entry and fluid uptake by transepithelial salt and water reabsorption. Conventional wisdom suggests the reabsorption is via epithelial Na channels (ENaC), but if all Na reabsorption were via ENaC, then amiloride, an ENaC inhibitor, should block alveolar fluid clearance (AFC). However, amiloride blocks only half of AFC. The reason for failure to block is clear from single-channel measurements from alveolar epithelial cells: ENaC channels are observed, but another channel is present at the same frequency that is nonselective for Na over K, has a larger conductance, and has shorter open and closed times. These two channel types are known as highly selective channels (HSC) and nonselective cation channels (NSC). HSC channels are made up of three ENaC subunits since knocking down any of the subunits reduces HSC number. NSC channels contain α-ENaC since knocking down α-ENaC reduces the number of NSC (knocking down β- or γ-ENaC has no effect on NSC, but the molecular composition of NSC channels remains unclear). We show that NSC channels consist of at least one α-ENaC and one or more acid-sensing ion channel 1a (ASIC1a) proteins. Knocking down either α-ENaC or ASIC1a reduces both NSC and HSC number, and no NSC channels are observable in single-channel patches on lung slices from ASIC1a knockout mice. AFC is reduced in knockout mice, and wet wt-to-dry wt ratio is increased, but the percentage increase in wet wt-to-dry wt ratio is larger than expected based on the reduction in AFC.

Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae

“…However, the studies of Johnson et al (47) and Lazrak et al (55) showed that rodent ATI and ATII cells express similar channel densities of highly selective Na ϩ channels, with a unitary conductance of~4 pS, most likely composed of the ␣-, ␤-, ␥-ENaC subunits, and nonselective ENaC cation channels, with a conductance of 16 -21 pS, composed of ␣-subunits only (42). It has also been reported that the nonselective channels consist of a combination of the ␣-ENaC subunit and one or more acid-sensing ion channel 1 (ASIC1a) proteins (103). Human alveolar cells also express ENaC (23) and actively transport Na ϩ , albeit at rates lower than in rodent lungs (89).…”

Epithelial Na+ Channel (ENaC) Formed by One or Two Subunits Forms Functional Channels That Respond to Shear Force

“…This raises the possibility that ENaC and their related ASIC proteins (Mano and Driscoll, 1999) may complex to from noncanonical cation channels. This possibility is strongly supported by a study providing evidence for the function of a non-selective cation channels formed by ENaC and ASIC subunits (Trac et al, 2017). These observations indicate that in tissues where only one or two ENaC subunits were identified, these may not only be able for form functional non-canonical ENaC channels but also associate with ASIC subunits and form ENaC/ASIC complexes.…”

Transport of AOPP-Albumin into Human Alveolar Epithelial A549 Cell

“…In addition, the excess alveolar fluid clearance is an active metabolic process concerning vectorial transport of Na + with water out of alveolar air space, following the osmotic gradient (19). Na + transport from the apical surface to alveolar epithelial cells is associated with amiloride-sensitive Na + channels (ENaC) and in part, by other, less well-characterized cationic channels (20,21). Thus, the mechanism underlying alveolar fluid clearance mediated by Na + transport is becoming clearer.…”