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Received October 7, 2002
Accepted after revision December 17, 2002
1 Department of Neurology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
2 Department of Applied Physiology, Ulm University, Ulm, Germany
* To whom correspondence should be addressed. E-mail: mohammadi.bahram{at}mh-hannover.de.
Missense mutations of the human skeletal muscle voltage-gated Na+ channel (hSkM1) cause a variety of neuromuscular disorders. The mutation R1448H results in paramyotonia congenita and causes cold-induced myotonia with following paralysis. The mutation M1360V causes an overlapping syndrome with both K+-induced muscle weakness and cold-induced myotonia. The molecular mechanisms of the temperature dependence of these disorders are not well understood. Therefore we investigated physiological parameters of these Na+ channel mutations at different temperatures. Channel proteins were recombinantly expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. We compared the wild-type (WT) channel with both mutants at different temperatures. Both mutations had slower inactivation and faster recovery from inactivation compared to WT channels. This effect was more pronounced at R1448H, leading to a larger depolarization of the cell membrane causing myotonia and paralysis. The voltage dependence of activation of R1448H was shifted to more negative membrane potentials at lower temperature but not at M1360V or WT. The window current by mutation R1448H was increased at lower temperatures. The results of this study may explain stronger cold-induced clinical symptoms by R1448H in contrast to M1360V.
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