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The M1 and pre-M1 segments contribute differently to ion selectivity in ASICs and ENaCs

  • The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological function. Members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily of trimeric ion channels are typically sodium selective, but to a surprisingly variable degree. While acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium ratio ∼10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). This discrepancy may be expected to originate from differences in the pore-lining second transmembrane segment (M2). However, these show a relatively high degree of sequence conservation between ASICs and ENaCs, and previous functional and structural studies could not unequivocally establish that differences in M2 alone can account for the disparate degrees of ion selectivity. By contrast, surprisingly little is known about the contributions of the first transmembrane segment (M1) and the preceding pre-M1 region. In this study, we used conventional and noncanonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in hENaC show that these regions contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work suggests that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. These results further highlight how M1 and pre-M1 are likely to differentially affect pore structure in these related channels.

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Document Type:Article
Author:Zeshan P. Sheikh, Matthias Wulf, Søren Friis, Mike Althaus, Timothy Lynagh, Stephan A. Pless
Parent Title (English):The Journal of General Physiology
Article Number:e202112899
Publisher:Rockefeller University Press
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2021/08/26
Embargo Date:2022/04/04
Copyright:© 2021 Sheikh et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license.
Funding:This work was supported by Lundbeckfonden (R171-2014558, to T. Lynagh; R139-2012-12390, to S.A. Pless), the Danmarks Frie Forskningsfond (4092-00348B, to T. Lynagh), and Carlsbergfondet (2013_01_0439, to S.A. Pless).
Keyword:Biophysics; Membrane Transport
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2021/10/19
Licence (German):License LogoCreative Commons - CC BY-NC-SA - Namensnennung - Nicht kommerziell - Weitergabe unter gleichen Bedingungen 4.0 International