Defective fast inactivation recovery and deactivation account for sodium channel myotonia in the I1160V mutant.
The skeletal muscle sodium channel mutant I1160V cosegregates with a disease phenotype producing myotonic discharges (observed as muscle stiffness) that are worsened by elevated K+ levels but unaffected by cooling. The I1160V alpha-subunit was co-expressed with the beta1-subunit in Xenopus oocytes. An electrophysiological characterization was undertaken to examine the underlying biophysical characteristics imposed by this mutation. Two abnormalities were found. 1) The voltage dependence of steady-state fast inactivation was reduced in I1160V, which resulted in faster rates of closed-state fast inactivation onset and recovery in I1160V compared with wild-type channels. 2) The rates of deactivation were slower in I1160V than in wild-type channels. Using a computer-simulated model, the combination of both defects elicited myotonic runs under conditions of elevated K+, consistent with the observed phenotype of the mutant.
Richmond
J E
JE
Department of Biology, University of Utah, Salt Lake City 84112, USA.
VanDeCarr
D
D
Featherstone
D E
DE
George
A L
AL
Ruben
P C
PC
D000818:Animals; D001483:Base Sequence; D055592:Biophysical Phenomena; D001703:Biophysics; D003198:Computer Simulation; D017931:DNA Primers / Q000235:genetics; D004594:Electrophysiology; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D008564:Membrane Potentials; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009222:Myotonia / Q000235:genetics* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D017354:Point Mutation; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D014982:Xenopus laevis
D017931:DNA Primers; D026941:Sodium Channel Blockers; D015222:Sodium Channels