Anesthetics exhibit considerable diversity in the nature of their anesthetic effects. The underlying mechanism of anesthetic action presumably involves alteration of one or more membrane conductances. Relative differences among anesthetics in their effects on these different targets may underlie the important clinical differences among anesthetics. Calcium channels are particularly attractive as potential targets of anesthetic action because of their central role in synaptic transmission. Some voltage-dependent calcium channels are inhibited by anesthetics within clinical concentrations. Inhibition of particular components of Ca plus current may contribute to some of the diverse effects of different anesthetics including anticonvulsant activity and analgesic activity. Steroid anesthetics provide a particularly interesting group for evaluation of potential targets of anesthetic action, because the structurally defined nature of steroids make them more amenable to structure/function investigations and more useful for the ultimate identification of binding sites. Recent studies indicate that specific steroids exhibit remarkable selectivity in blocking particular components of calcium current. Based on these studies, this proposal addresses a series of aims concerned with the molecular mechanisms of action of steroids on calcium channels. First, we will examine the structure-activity relationships for blockade of particular calcium current components by steroids. Second, we will extend earlier work in which we are defining the pharmacological similarities and differences between different low voltage-activated calcium currents among different neurons. Third, using steroids which selectively block particular components of calcium current in native cells, we will examine the effects of those agents on cloned neuronal calcium channel variants. Finally, we will examine the contribution of different high-voltage-activated calcium currents in synaptic transmission in cultures of hippocampal neurons and the effects of steroids on that transmission. These experiments will provide a whole new series of agents for selective inhibition of different calcium current components which will help advance our understanding of the clinical and behavioral roles of different calcium channel subtypes.
Showing the most recent 10 out of 193 publications
