Date of Award:

5-1-1997

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Biology

Committee Chair(s)

P. Ruben

Committee

P. Ruben

Committee

E. Brodie

Committee

L. Powers

Committee

J. Takemoto

Committee

D. Vaughan

Abstract

Voltage-gated skeletal muscle sodium channels are large transmembrane proteins that are responsible for the initiation and propagation of skeletal muscle action potentials. Sodium channels undergo three kinetically and pharmacologically distinct processes: activation/deactivation, fast inactivation, and slow inactivation. The work in this dissertation characterized each of these processes in heterologously expressed voltage-gated skeletal muscle sodium channels, then examined biophysical changes in mutant sodium channels responsible for paramyotonia congenita, an inherited human disease of muscle hyperexcitability. All sodium channel kinetic processes were studied, with particular emphasis on slow inactivation, which had not previously been well characterized. Paramyotonia congenita appears to result from defects in sodium channel open-state fast inactivation and deactivation, such that sodium channels tend to remain open during the downstroke of a muscle action potential, leading to destabilization of repolarization and therefore hyperexcitability.

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Biology Commons

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