Voltage-gated sodium channels are heteromultimeric integral membrane proteins that are responsible for the initial phase of the action potential in most excitable cells. A variety of inherited disorders affecting skeletal muscle contraction (hyperkalemic periodic paralysis, paramyotonia congenita, K+-aggravated myotonia), cardiac excitability (congenital long QT syndrome, idiopathic ventricular fibrillation, familial conduction system disease) and certain forms of epilepsy have been associated with mutations in various human sodium channel genes. This proposal is a competing renewal of R37-NS32387 that for 16 years has funded our efforts to elucidate the molecular genetic, physiologic and pharmacologic mechanisms of human sodium """"""""channelopathies"""""""". We propose to continue our highly successful research program with a focus on epilepsies associated with mutant brain sodium channels. The experimental sequence begins with studies to elucidate the functional consequences of novel SCN3A mutations associated with genetic epilepsy syndromes (Specific Aim 1). These studies will include experiments to investigate the importance of alternative splicing in the functional behavior of mutant sodium channels. We plan to move our investigations to an in vivo platform with experiments described in Specific Aim 2 where we propose to test the hypothesis that strain-dependence of epilepsy in transgenic mice expressing a mutant sodium channel correlates with varying neuronal excitability due to divergent levels of persistent sodium current evoked by the mutant transgene. Together, the proposed experiments provide us with opportunities to determine molecular defects responsible for epilepsies associated with mutant sodium channels, and to elucidate potential mechanisms responsible for the influence of genetic modifiers on epilepsy severity.
Epilepsy is a common neurological disorder affecting nearly 1% of the U.S. population. Understanding how genetic factors contribute to the pathogenesis of epilepsy has great importance for diagnosis and treatment of this condition. This grant funds studies of epilepsies caused by genetic mutations in sodium channels, a type of protein important for generating electrical impulses in the brain.
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|Anderson, Lyndsey L; Thompson, Christopher H; Hawkins, Nicole A et al. (2014) Antiepileptic activity of preferential inhibitors of persistent sodium current. Epilepsia 55:1274-83|
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|Vanoye, Carlos G; Kunic, Jennifer D; Ehring, George R et al. (2013) Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling. J Gen Physiol 141:193-202|
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