General anesthetics produce nervous system depression, at least in part, from inhibition of excitatory synaptic transmission. The effect of general anesthetics on excitatory synaptic pathways is thought to result primarily from inhibition of synaptic transmission rather than from inhibition of neuronal conduction. The underlying mechanism of anesthetic action presumably involves alteration of one or more membrane conductances. Although effects of general anesthetics on a number of different ions channels have been described, as yet, the identity of the molecular targets of anesthetics which are likely to underlie the production of anesthesia remains undefined. Furthermore, the mechanisms by which anesthetics affect ion channels are largely unknown. Calcium channels are particularly attractive as potential targets of anesthetic action because of their central role in synaptic transmission. Recent studies suggest that voltage-dependent calcium channels may be a potential site of general anesthetic action. Effects of volatile anesthetics on some calcium currents appear to occur at clinically reasonable concentrations. This proposal addresses two major questions concerning the molecular mechanism of anesthetic action. First, it will determine whether specific subtypes of calcium channels are reasonable candidates for potential targets of anesthetic action. Second, as a first step towards defining the molecular mechanism by which anesthetics inhibit calcium channels, the functional alterations of calcium current produced by volatile anesthetics will be determined. These issues will be addressed by using both whole- cell and single-channel electrophysiological studies of particular subtypes of calcium currents. Subtypes of calcium currents will be isolated by a combination of pharmacological criteria and the use of particular types of neurons which express largely a single type of calcium current. The results will provide definitive information about the sensitivity of four kinds of calcium current, T, L, N, and P, to both volatile anesthetics and to pentobarbitone. The results should answer the question of which, if any, neuronal calcium channels are reasonable candidates for molecular targets of anesthetic action.
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