Key result
K1237C mutation increases sodium channel Ca2+ permeability ~60-fold versus wild-type despite restoring positive charge.
Absolute Event Rate: 0.6% vs 0.01%
The chemical identity of the residue at position 1237 in the sodium channel is crucial for selectivity, and simply rendering the side chain positive does not suffice to restore Na+ selectivity.
Does not guide clinical management of channelopathies; extends evidence that residue chemistry, not charge alone, governs Na+ selectivity.
A conserved lysine residue in the "P loop" of domain III renders sodium channels highly selective. Conversion of this residue to glutamate, to mimic the homologous position in calcium channels, enables Ca2+ to permeate sodium channels. Because the lysine-to-glutamate mutation converts a positively charged side chain to a negative one, it has been proposed that a positive charge at this position suffices for Na+ selectivity. We tested this idea by converting the critical lysine to cysteine (K1237C) in mu 1 rat skeletal sodium channels expressed in Xenopus oocytes. Selectivity of the mutant channels was then characterized before and after chemical modification to alter side-chain charge. Wild-type channels are highly selective for Na+ over Ca2+ (PCa/PNa < 0.01). The K1237C mutation significantly increases permeability to Ca2+ (PCa/PNa = 0.6) and Sr2+. Analogous mutations in domains I (D400C), II (E755C), and IV (A1529C) did not alter the selectivity for Na+ over Ca2+, nor did any of the domain IV mutations (G1530C, W1531C, and D1532C) that are known to affect monovalent selectivity. Interestingly, the increase in permeability to Ca2+ in K1237C cannot be reversed by simply restoring the positive charge to the side chain by using the sulfhydryl modifying reagent methanethiosulfonate ethylammonium. Single-channel studies confirmed that modified K1237C channels, which exhibit a reduced unitary conductance, remain permeable to Ca2+, with a PCa/PNa of 0.6. We conclude that the chemical identity of the residue at position 1237 is crucial for channel selectivity. Simply rendering the 1237 side chain positive does not suffice to restore selectivity to the channel.
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Pérez‐García et al. (1997) studied this question. K1237C mutation and sulfhydryl modification vs. Wild-type channels was evaluated on Permeability to Ca2+ (PCa/PNa). The K1237C mutation in sodium channels significantly increased permeability to Ca2+ (PCa/PNa = 0.6) compared to wild-type channels (PCa/PNa < 0.01), which was not reversed by restoring positive charge.
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