Paramyotonia congenita: the R1448P Na+ channel mutation in adult human skeletal muscle.
Twitch force and Na+ currents were investigated in a muscle biopsy specimen from a patient with paramyotonia congenita carrying the dominant Arg-1448-Pro mutation in the skeletal muscle sodium channel. Cooling of the muscle fibers caused sustained membrane depolarization that resulted in reduced twitch force. Membrane repolarization, produced by a K+ channel opener, partly prevented and antagonized the drop in twitch force. Patch-clamp recordings on sarcolemmal blebs revealed a distinctly slower Na+ current decay on paramyotonia congenita muscle compared to control muscle. In addition, patches with mutant Na+ channels showed a significantly higher frequency of steady-state openings, which increased with cooling. Activation of mutant channels was not affected, whereas the steady-state inactivation curve was shifted by -5 mV and showed less voltage dependence. We suggest that the weakness of cooled muscle can be explained by a combination of the increased steady-state Na+ current and the left-shifted inactivation curve.
Lerche
H
H
Department of Applied Physiology, University of Ulm, Germany.
Mitrovic
N
N
Dubowitz
V
V
Lehmann-Horn
F
F
D000328:Adult; D001120:Arginine / Q000235:genetics; D001706:Biopsy; D003080:Cold Temperature; D005260:Female; D006358:Hot Temperature; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007537:Isometric Contraction / Q000502:physiology; D008839:Microelectrodes; D018908:Muscle Weakness / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000737:chemistry / Q000502:physiology*; D009224:Myotonia Congenita / Q000235:genetics* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D017354:Point Mutation / Q000502:physiology; D011392:Proline / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D016138:Walking
D015222:Sodium Channels; D001120:Arginine; D011392:Proline