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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032387-17
Application #
7783647
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Stewart, Randall R
Project Start
1994-01-01
Project End
2011-05-31
Budget Start
2010-03-01
Budget End
2011-05-31
Support Year
17
Fiscal Year
2010
Total Cost
$493,128
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Anderson, Lyndsey L; Hawkins, Nicole A; Thompson, Christopher H et al. (2017) Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome. Sci Rep 7:1682
Huang, Jianying; Vanoye, Carlos G; Cutts, Alison et al. (2017) Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability. J Clin Invest 127:2805-2814
Thompson, Christopher H; Hawkins, Nicole A; Kearney, Jennifer A et al. (2017) CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice. Proc Natl Acad Sci U S A 114:1696-1701
Vanoye, Carlos G; Gurnett, Christina A; Holland, Katherine D et al. (2014) Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis 62:313-22
George Jr, Alfred L (2014) Lessons learned from genetic testing for channelopathies. Lancet Neurol 13:1068-1070
George Jr, Alfred L (2014) Recent genetic discoveries implicating ion channels in human cardiovascular diseases. Curr Opin Pharmacol 15:47-52
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
Mistry, Akshitkumar M; Thompson, Christopher H; Miller, Alison R et al. (2014) Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice. Neurobiol Dis 65:1-11
Torkamani, Ali; Bersell, Kevin; Jorge, Benjamin S et al. (2014) De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol 76:529-540
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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