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Science 2 November 1990:
Vol. 250. no. 4981, pp. 688 - 691
DOI: 10.1126/science.2173138
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Articles

Science, Vol 250, Issue 4981, 688-691
Copyright © 1990 by American Association for the Advancement of Science

articles

Changes in sodium channel gating produced by point mutations in a cytoplasmic linker

Moorman JR, GE Kirsch, AM Brown, and RH Joho

Department of Medicine, University of Texas Medical Branch, Galveston 77550.

Voltage-gated sodium channels are transmembrane proteins of approximately 2000 amino acids and consist of four homologous domains (I through IV). In current topographical models, domains III and IV are linked by a highly conserved cytoplasmic sequence of amino acids. Disruptions of the III-IV linker by cleavage or antibody binding slow inactivation, the depolarization-induced closed state characteristic of sodium channels. This linker might be the positively charged "ball" that is thought to cause inactivation by occluding the open channel. Therefore, groups of two or three contiguous lysines were neutralized or a glutamate was substituted for an arginine in the III-IV linker of type III rat brain sodium channels. In all cases, inactivation occurred more rapidly rather than more slowly, contrary to predictions. Furthermore, activation was delayed in the arginine to glutamate mutation. Hence, the III-IV linker does not simply act as a charged blocker of the channel but instead influences all aspects of sodium channel gating.


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