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2021 - Differential contributions of M1 and pre-M1 to ion selectivity in ASICs and ENaCs

icon sp96 SyncroPatch 384PE (a predecessor model of the SyncroPatch 384 instrument) prepublication in bioRxiv (2021)

Sheikh Z.P. , Wulf M., Friis S., Althaus M., Lynagh T., Pless S.A.


bioRxiv (2021) doi: 10.1101/2021.02.16.431267


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 around 10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). The most obvious explanation for 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 use conventional and non-canonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mammalian ASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in human ENaC show that they contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work supports the notion that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. This further highlights how subtle sequence variations in related channels can translate into notably different functional outcomes.

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