Different effects on gating of three XXXX -causing mutations in the inactivation gate of the @entity1 muscle sodium channel.

@entity1 @entity52009 @entity3529 @entity4024 @entity46840 @entity8525 @entity7285 @entity57960
1. Three mutations at the same site in the inactivation gate of the alpha-subunit of the @entity1 muscle @entity4024 channel, @entity46840 , @entity52009 and @entity57960 , cause three phenotypes of @entity3529 -aggravated @entity8525 : @entity46840 as the most severe and @entity57960 as the most benign form. 2. Recombinant wildtype (WT) and mutant ( @entity46840 , @entity52009 and @entity57960 ) @entity1 @entity4024 + channels were expressed in @entity1 embryonic kidney cells (HEK293). @entity46840 and @entity52009 channels showed a distinct increase in the time constants of inactivation (tau @entity7285 ) and in the ratios of steady-state to peak currents (Iss/Ipeak) (e.g. at 0 mV, @entity46840 vs. WT; tau h1, 1.29 +/- 0.10 vs. 0.52 +/- 0.01 ms; Iss/Ipeak, 2.90 +/- 0.40 vs. 0.93 +/- 0.19%). @entity57960 channels showed only an increase in tau h1 (0.74 +/- 0.07 ms). For @entity46840 and @entity52009 channels, the steady-state inactivation curves, as well as the voltage dependence of the rate of recovery from inactivation, were shifted by +15 mV. For @entity57960 the h infinity curve was shifted by only +5 mV. 3. @entity46840 and @entity52009 channels showed prolonged current rise times and later first openings suggesting slowing of activation. For @entity46840 channels only, the steady-state activation curve was shifted by -7 mV. For all mutants the deactivation time constants were increased. 4. We conclude that (i) the combination of alterations in inactivation and activation produces the slowing of the current decay, (ii) the slowed inactivation is most responsible for @entity8525 , and (iii) the shift of the steady-state activation curve, seen only with @entity46840 channels, may explain the severity of this phenotype. 5. The results suggest that two of the mutations in the Na+ channel inactivation gate also alter channel activation and deactivation.
