G proteins are involved many aspects of signal transduction. They play a major role in regulation of vascular tone, cardiac function and central nervous system control of the cardiovascular system. Information is beginning to emerge regarding their role in pathophysiology of the cardiovascular system. There has been an explosion of information about the structure and diversity of receptor and G protein subtypes involved in this system. This new information has opened up whole realms of specificity for pharmacologic intervention. The ability to block or activate specific subtypes of the receptors or G proteins should yield many new, much more selective, agents for basic pharmacologic studies and targeted clinical therapy. The alpha2 adrenergic receptor, which is a target for antihypertensive agents, is a member of a class of receptors coupled to G protein signal transduction systems. The proposed work will develop synthetic peptides based on the structure of the alpha2 adrenergic receptors and related receptors. We have identified two peptides from the alpha2 adrenergic receptor which inhibit the alpha2 receptor-Gi protein signalling system. The mechanism of action of these peptides will be characterized in detail because this novel approach to the development of drugs is still in its infancy and mechanisms have not yet been explored systematically. Structure-activity-relations of the alpha2 receptor peptides will be determined by synthetic deletion and mutagenesis to design optimally specific and potent drugs with effects on signal transduction by Go, Gi, Gs, and Gp. The identification of the structural determinants of active peptide fragments of the alpha2 adrenergic receptor should lead to important new pharmacologic and therapeutic agents and serve as a model for the development of peptides for other G protein-linked signal transduction systems.
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