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Identifying the elusive link between amino acid sequence and charge selectivity in pentameric ligand-gated ion channels. | LitMetric

AI Article Synopsis

  • The superfamily of pentameric ligand-gated ion channels (pLGICs) is unique because they can selectively allow either cations or anions to pass through, even though they have a similar structure.
  • Despite extensive research on how these channels determine which ions can pass, there is still no clear consensus, as previous studies have shown conflicting results.
  • New evidence from experiments involving mutations and electrical measurements suggests that the charge and arrangement of specific side chains in the channel's structure play a key role in determining ion selectivity, and that changes in these side chains can significantly alter how these channels function.

Article Abstract

Among neurotransmitter-gated ion channels, the superfamily of pentameric ligand-gated ion channels (pLGICs) is unique in that its members display opposite permeant-ion charge selectivities despite sharing the same structural fold. Although much effort has been devoted to the identification of the mechanism underlying the cation-versus-anion selectivity of these channels, a careful analysis of past work reveals that discrepancies exist, that different explanations for the same phenomenon have often been put forth, and that no consensus view has yet been reached. To elucidate the molecular basis of charge selectivity for the superfamily as a whole, we performed extensive mutagenesis and electrophysiological recordings on six different cation-selective and anion-selective homologs from vertebrate, invertebrate, and bacterial origin. We present compelling evidence for the critical involvement of ionized side chains-whether pore-facing or buried-rather than backbone atoms and propose a mechanism whereby not only their charge sign but also their conformation determines charge selectivity. Insertions, deletions, and residue-to-residue mutations involving nonionizable residues in the intracellular end of the pore seem to affect charge selectivity by changing the rotamer preferences of the ionized side chains in the first turn of the M2 α-helices. We also found that, upon neutralization of the charged residues in the first turn of M2, the control of charge selectivity is handed over to the many other ionized side chains that decorate the pore. This explains the long-standing puzzle as to why the neutralization of the intracellular-mouth glutamates affects charge selectivity to markedly different extents in different cation-selective pLGICs.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111664PMC
http://dx.doi.org/10.1073/pnas.1608519113DOI Listing

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