Ca2+-sensitivity of human NaV1.4F1705I inactivation.
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(A) A schematic of the structured region of the C-terminus of hNaV1.4 between amino acids residues 1788 and 2040, the predicted helices are labeled H1–H6. The location of the EFL residues in and around H1 harbors species specific variations in the key Ca2+ sensing residues in hNaV1.4 (G1613S and A1636D) compared with the rat isoform. The CaM binding motif IQ in H6 and, the cold aggravated myotonia mutation F1705I (rat: F1698I) in H5 are illustrated. (B) Representative whole-cell currents through wild type and mutant hNaV1.4F1705I channels expressed in HEK293 cells in [Ca2+]i free conditions. Na+ currents were elicited by the protocol in the inset. (C) [Ca2+]i does not alter the I–V relationship of hNaV1.4F1705I. (D) Representative steady-state inactivation currents from different holding potentials through mutant hNaV1.4F1705I channels in the presence of 0.5 µM or absence of Ca2+. (E) Activation and steady-state inactivation curves of wild type and hNaV1.4F1705I channels in the absence and presence of 0.5 µM intracellular Ca2+. The V1/2 of inactivation of hNaV1.4F1705I is sensitive to [Ca2+]i and significantly shifted in the hyperpolarizing direction in the presence of Ca2+ (p<0.005). The activation relationships are fitted with dotted lines, the V1/2 of activation are unaffected by change in [Ca2+]i. (F) and (G) illustrate the window currents through wild type and hNaV1.4F1705I in presence (F) and absence (G) of intracellular Ca2+, respectively. Dotted lines represent the wild type channel. The symbols and color are the same in plots C, E, F, and G.