Influx of sodium ions through voltage-gated sodium channels initiates membrane depolarization and the rising phase of the action potential in excitable cells. These integral membrane proteins are comprised of an a-subunit and smaller b-subunits, forming a large multimeric complex that is over 300 kD in size. The ion-conducting aqueous pore is harbored within the a-subunit, which by itself is sufficient to demonstrate the essential elements of sodium channel function - channel opening, ion selectivity and rapid inactivation. There are 10 known voltage-gated sodium channel genes in the vertebrate genome.

My research interests centers around the transgenic mouse technology to study these essential ion channels of excitable cells. Recently, we have generated a mouse model of the human epileptic syndrome of Severe Myoclonic Epilepsy in Infancy (SMEI) through targeted deletion of the Nav1.1 gene. Heterozygous loss of function mutations in SCN1A, the gene encoding for the brain type I sodium channel (Nav1.1) and the functional haploinsufficiency of the Nav1.1 sodium currents underlies this progressive epilepsy that begins in infancy with generalized and focal seizures, and is medically refractory with unfavorable long-term outcome. This animal model substantially phenocopies the human SMEI condition and spontaneous, recurrent epileptic seizures is acquired in juvenile heterozygous mutant mice with varying penetrance and severity depending on genetic strain background. The Nav1.1 heterozygous mice are an opportune animal model in which to study the developmental pathophysiology of SMEI and to test the efficacies of potential antiepileptic therapies.

We have additional interests in transgenic mouse lines of auxiliary beta subunits of the sodium channels as well as a voltage-gated calcium channel to study their roles in other channelopathies of excitable cells, like the cardiac myocytes.