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 R01-NS32387 that for 8 years has funded our efforts to elucidate the molecular genetic, physiologic and pharmacologic mechanisms of human sodium """"""""channelopathies"""""""". We have recently shifted our focus from studies of the two striated muscle sodium channel genes (SCN4A, SCN5A) to investigations of brain sodium channel genes and their role in inherited epilepsies. We propose to perform a series of carefully integrated experiments employing molecular genetic, recombinant DNA and cellular electrophysiological approaches to elucidate the molecular defects responsible for seizure disorders linked to three distinct neuronal sodium channel genes (SCN1B, SCNIA, SCN2A).
In Specific Aim 1, we propose to perform molecular genetic screening in a large cohort of families segregating seizure phenotypes consistent with generalized epilepsy with febrile seizures plus (GEFS+), severe myoelonic epilepsy of infancy (SMEI) and other less well characterized disorders that may be associated with mutations in brain sodium channels.
In Specific Aim 2, we plan to perform biophysical and pharmacological characterization of epilepsy-associated mutations using recombinant human neuronal sodium channels expressed heterologously in mammalian cells. Our laboratory is uniquely qualified to elucidate the molecular mechanism of SCN1A-associated epilepsy using recombinant human SCN1A, a reagent that we have recently developed. Finally in Specific Aim 3, we will elucidate the molecular mechanisms responsible for dysfunction of the human sodium channel [31 subunit in some forms of familial epilepsy. Altogether, this work is designed to establish important correlations between genotype, clinical phenotype and biophysical properties of mutant sodium channels in human epilepsies and will have important pathophysiologic and therapeutic implications for hereditary disorders of sodium channels. ? ? ?
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Thompson, Christopher H; Porter, J Christopher; Kahlig, Kristopher M et al. (2012) Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression. J Biol Chem 287:42001-8 |
| George Jr, Alfred L (2012) Leaky channels make weak muscles. J Clin Invest 122:4333-6 |
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