MOLECULAR PHYSIOLOGY OF NEUROMUSCULAR DISEASES

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DESCRIPTION: The myotonias and periodic paralyses are heritable diseases of skeletal muscle in which mutations of voltage-gated ion channels alter the electrical excitability of the sarcolemma. The long-term goals of this project are to characterize the functional defects of mutant channels in these disorders and to determine how abnormal channel behavior produces symptoms. Hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium-aggravated myotonias (PAM) are all caused my missense mutations in the b subunit of the adult skeletal muscle sodium channel (SkM1). By recording Na currents from patient-derived myotubes or from heterologously expressed mutant channels, we and other have shown that the primary defect in these diseases is disruption of fast inactivation. Aim 1 of this proposal is to identify the functional defects for additional, as-yet uncharacterized, mutations and to define further the spectrum of gating defects. Aim 2 seeks to improve the treatment of these diseases by studying the mechanism of action of mexiletine (a use-dependent blocker) and acetazolamide on mutant Na channels. Because Na channel inactivation is a critical determinant in the predilection for myotonia or paralysis, in Aim 2 we will further investigate the molecular mechanisms underlying normal fast and slow inactivation using cysteine-scanning mutagenesis within the proposed inactivation gate (cytoplasmic loop between domains III-IV). Aim 4 is to determine how primary defects in Na channel gating lead to the divergent phenotypes of myotonia and periodic paralysis. The strategy for exploring the pathophysiologic basis of these phenotypes is to refine further our computer simulation of muscle excitability, to use myogenic expression systems, and to develop animal-based models. The proposed studies are designed to provide a more complete understanding of the pathophysiologic basis for a group of human neuromuscular diseases: from gene defect to clinical symptoms. These studies will also further our knowledge of Na channel function at the molecular level, will identify pharmacological strategies for treating patients, and will serve as a model system for understanding more common disorders of excitability such as epilepsy or cardiac arrhythmia.