The final common pathway of electrical excitability in neurons is generation of conducted action potentials. Action potentials in nerve and muscle are initiated by activation of voltage-gated sodium channels, and the threshold and frequency of firing which encode information in the nervous system are critically dependent on sodium channel properties. The ion conductance activity of sodium channels is controlled on the millisecond time scale by two distinct but coupled gating processes: activation and inactivation. Activation controls the voltage- and time-dependence of conductance increase in response to depolarization, and inactivation controls the voltage- and time- dependence of the subsequent return of the sodium conductance to the basal level within one millisecond. Both processes are essential for normal electrical excitability of nerve and muscle cells, and elucidation of their molecular basis is a major challenge for molecular neurobiology. The essential nature of the inactivation process is illustrated by the striking effects of dominant mutations which impair this process in the periodic paralyses of skeletal muscle and long QT syndrome in the heart. One can anticipate that similar hyperexcitability syndromes may be caused by mutations in brain sodium channels and contribute to both inherited and spontaneously arising forms of epilepsy. In the current project period, we have made substantial progress on several topics related to the molecular basis for sodium channel inactivation, its modulation by second messenger- activated protein phosphorylation and by peptide neurotoxins, and its interaction with pore-blocking drugs. We have discovered the key amino acid residues in the inactivation gate which are essential for its function, elucidated the three-dimensional structure of the key region of the inactivation gate, identified candidate residues involved in formation of the inactivation gate receptor, defined the phosphorylation sites responsible for regulation of channel gating by protein phosphorylation initiated by the dopamine D1/cAMP-dependent protein kinase signaling pathway and the muscarinic acetylcholine/protein kinase C signaling pathway in neurons, and identified important components of the receptor site for scorpion toxins and local anesthetic drugs which interact with the inactivation process. In the next project period, we propose to build on this foundation of molecular information about sodium channel gating and further define the molecular basis of its physiological and pharmacological regulation. Our objectives are to elucidate the molecular interactions of the inactivation gate with the putative inactivation gate receptor, to define the three-dimensional structure of the inactivation gate, to probe the molecular mechanisms by which protein phosphorylation influences sodium channel gating and define the interactions of the relevant phosphorylation sites with the inactivation gate, to determine the molecular basis for high affinity binding of local anesthetics to inactivated channels and for molecular trapping of these drugs in their receptor site by closure of the channel activation and inactivation gates, and to analyze the coupling of movements of the S4 voltage sensors to voltage-dependent activation and inactivation using alpha- and beta-scorpion toxins as specific molecular probes. These proposed studies will give new insight into the molecular mechanisms of sodium channel gating and its modification by second messenger-activated protein phosphorylation and by drugs and neurotoxins.
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