1) is often invoked to explain selectivity for cations or anions, respectively, even when α7 ( 1, 2) and muscle ( 3) nicotinic acetylcholine receptors (AChRs) remain highly cation selective upon neutralization of all of the negatively charged side chains at this position. For example, the presence (in the wild-type cation-selective pLGICs) or absence (in the wild-type anion-selective pLGICs) of a “ring” of pore-lining glutamates at the intracellular end of the transmembrane portion of the pore (position –1′ Fig. Certainly, the relationship between primary sequence and cation-versus-anion selectivity in these channels is so difficult to encapsulate in a few rules that predicting charge selectivity from the mere inspection of sequences is not a trivial task, especially when it comes to mutant sequences or wild-type sequences from bacteria, Archaea, or invertebrate organisms. Thus, because all cation-selective NGICs discriminate poorly between Na + and K +, fast inhibitory synaptic transmission is mediated, exclusively, by the anion-selective pLGICs.įew aspects of pLGICs are as intriguing-and, at the same time, have remained as elusive and controversial-as the physicochemical basis of their opposite charge selectivities. Among these ion channels, only the superfamily of pentameric ligand-gated ion channels (“pLGICs”) has evolved to give rise to members that are highly selective for either cations or anions while retaining the same overall structure all other NGICs (that is, those gated by glutamate or ATP) are selective for cations. Anion-selective NGICs, on the other hand, are mostly inhibitory, but they can also be excitatory depending on a number of factors that include the values of the Cl – and HCO 3 – equilibrium (Nernst) potentials and the resting membrane potential. In excitable tissues, for example, cation-selective NGICs are excitatory because their opening leads to an influx of Na + that depolarizes the cell. The physiological role of a neurotransmitter-gated ion channel (NGIC) depends, to a large extent, on whether it is permeable to cations or anions. 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. 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. 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 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. 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. 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. 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.
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