(i) The gating mechanism of voltage dependent ion channels will be investigated, and (ii) the distribution of voltage gated channels in central neurons. Voltage dependent ion channels underlay many processes that are essential to life, frog conductance of nerve impulses, to analysis of information in the brain, to timing of the heartbeat. These essential channels open and close ('gate') in response to voltage changes, and some of the elements of their ability to respond to voltage signals is inherent in the structure of the channel peptide. Gating is also sensitive to the divalent composition in the external solution. A major focus of this grant is to understand this sensitivity (which is medically important in hypocalcemia) and to understand the role of divalent cations in channels gating. Precise understanding of gating and the divalent cation effect will guide drug design. Voltage gated channels are essential to the function of all nerve cells of the brain, but relatively little is known of their distribution. A fundamental question is the channel composition of dendritic membrane, which determines the response of the dendrite, and the cell, to synaptic information. Do the cells respond to dendritic input by generating action potentials? Are the action potentials caused by Na channels, or Ca channels? It is time to begin extending our knowledge of voltage gated channels to these functional questions in neurons.
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