The voltage-sensitive sodium channel is an integral component of impulse conduction by neuronal cells, transmitting the initial inward current during an action potential. The overall goal of Dr. Goldin's study is to determine the roles of specific structural regions of the channel that are involved in gating. There are four putative transmembrane amphipathic helices termed S4 in the sodium channel that have been proposed to function as voltage sensor regions involved in voltage-dependent activation of the channel. Dr. Goldin will test this by constructing mutations at comparable positions in each of the S4 regions, and by determining if each of the charges is contributing to the effective valence of activation. His second objective is to determine if these same voltage sensors are involved in the process of slow sodium channel inactivation. While fast inactivation of sodium channels is thought to be essentially independent of voltage, slow inactivation very likely involves some voltage sensitivity independent of activation. The effects of each of the S4 region mutations in slow inactivation will be tested to determine if the S4 regions are functioning as inactivation voltage gating charge of the channel. Dr. Goldin will accomplish this by using a newly developed voltage clamp to measure gating currents of channels containing mutations in each of the four S4 regions. These studies should enhance our knowledge about the normal function of the voltage-sensitive sodium channel, ultimately helping to understand the pathological processes that affect channel function in disease and to design pharmaceuticals that interact with channels of specific tissues.
