GRANT=6521568;P01GM The mechanisms by which general anesthetics have their clinically desired effects are not yet fully understood. The work proposed in this Program is designed to define the molecular target(s) for anesthetic steroids and to clarify the way in which action at these targets results in anesthesia. The underlying idea is that steroid anesthetics act at defined sites on proteins and, in particular, the proteins involved in formation transfer between neurons. The proposed research will build on a series of advances made in proceeding periods of the Program, which have provided insights into the sites and mechanisms of action for steroids. One objective of the Program is to define the actions of steroids on several classes of membrane channel, including GABA-A receptors, glutamatergic receptors and glycinergic receptors. The second objective of the Program is to define the structural basis for steroid interaction with one specific target, the GABA-A receptor. This work will involve complementary studies to modify the structure of the receptor and to examine the structures labeled by site-specific photo-activated steroid analogues. The third objective of the Program is to clarify the mechanisms by which steroids have their actions on their molecular targets. The final objective of the Program is to clarify the mechanisms by which steroids have their actions on their molecular targets. The final objective is to correlate the pharmacological and physiological results with the production of anesthesia or other states defined only at the level of the whole animal. Although the focus is anesthetic steroids, the Program will include examination of additional anesthetics for comparison to the steroids. Each project addresses one or other aspect of the action of anesthetic steroids at the cellular and molecular level. The Program as a whole will integrate these complementary studies and provide the resources for continued development of novel compounds and for assays of dry effects on behavioral states.
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