• ENaC

    Cumulative dose-dependent block of ENaC by Amiloride, measured on the SyncroPatch 96, a predecessor model of the SyncroPatch 384PE

2021 - The M1 and pre-M1 segments contribute differently to ion selectivity in ASICs and ENaCs

icon sp96 SyncroPatch 384PE (a predecessor model of the SyncroPatch 384 instrument) Publication in Journal of General Physiology (2021)

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


Journal of General Physiology (2021) doi: 10.1085/jgp.202112899


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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