Gamma subunit second transmembrane domain contributes to epithelial sodium channel gating and amiloride block.

Gamma subunit second transmembrane domain contributes to epithelial sodium channel gating and amiloride block. Am J Physiol Renal Physiol. 2013 Oct 9; Authors: Shi S, Kleyman TR Abstract The epithelial sodium channel (ENaC) is comprised of three homologous subunits. Channels composed solely of α and β subunits (αβ channels) exhibit a very high open probability (Po) and reduced sensitivity to amiloride, in contrast to channels composed of α and γ subunits or of all three subunits (i.e., αγ and αβγ channels). A mutant channel comprised of α and β subunits, and a chimeric γ subunit where the region immediately preceding (β12 and wrist) and encompassing the second transmembrane domain (TM2) was replaced with the corresponding region of the β subunit (γ-βTM2) displayed characteristics reminiscent of αβ channels, including a reduced potency of amiloride block and a loss of Na(+) self-inhibition (reflecting an increased Po). Substitutions at key pore-lining residues of the γ-βTM2 chimera enhanced the Na(+) self-inhibition response, whereas key γ subunit substitutions reduced the response. Furthermore, multiple sites within the TM2 domain of the γ subunit were required to confer high amiloride potency. In summary, we have identified novel pore-lining residues of the γ subunit of ENaC that are important for proper channel gating and its interaction with amiloride. PMID: 24107424 [PubMed - as supplied by publisher]
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research