The M1 and pre-M1 segments contribute differently to ion selectivity in ASICs and ENaCs
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The M1 and pre-M1 segments contribute differently to ion selectivity in ASICs and ENaCs. / Sheikh, Zeshan P.; Wulf, Matthias; Friis, Søren; Althaus, Mike; Lynagh, Timothy; Pless, Stephan A.
In: Journal of General Physiology, Vol. 153, No. 10, e202112899, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The M1 and pre-M1 segments contribute differently to ion selectivity in ASICs and ENaCs
AU - Sheikh, Zeshan P.
AU - Wulf, Matthias
AU - Friis, Søren
AU - Althaus, Mike
AU - Lynagh, Timothy
AU - Pless, Stephan A.
N1 - Funding Information: This work was supported by Lundbeckfonden (R171-2014-558, to T. Lynagh; R139-2012-12390, to S.A. Pless), the Danmarks Frie Forskningsfond (4092-00348B, to T. Lynagh), and Carls-bergfondet (2013_01_0439, to S.A. Pless). Publisher Copyright: © 2021 Sheikh et al.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Biophysics
KW - Membrane transport
U2 - 10.1085/jgp.202112899
DO - 10.1085/jgp.202112899
M3 - Journal article
C2 - 34436511
AN - SCOPUS:85116989583
VL - 153
JO - Journal of General Physiology
JF - Journal of General Physiology
SN - 0022-1295
IS - 10
M1 - e202112899
ER -
ID: 283212031