Catecholamines such as the neurotransmitter norepinephrine and the hormone epinephrine are of vital importance in the neural and humoral control of the entire circulation. The diverse effects of these agents on cardiovascular control centers in the brain, on the vasculature, heart and platelets are mediated by a multiplicity of receptor subtypes classified as wither alpha1, alpha2 or beta-adrenergic receptors. Moreover, drugs which act on these receptors as agonists and antagonists are amongst the most widely used agents in the treatment of cardiovascular disorders such as hypertension and congestive heart failure. This grant is requested to support a program in basic research directed at elucidating the molecular basis for the activation and desensitization of the alpha-adrenergic receptors. Although the impetus to and long range goal of our studies is to shed light on the basic biochemical process underlying adrenergic control of the circulation, the research proposed here will utilize as model systems the cloned and expressed genes for these receptors. The research proposal has several interrelated goals. These are to increase understanding of the ways in which agonist binding ot the receptors transmits signals via intermediary quanine nucleotide regulatory proteins to physiological effectors such as enzymes (phospholipase C) or ion channels and to elucidate the mechanisms by which such signalling is rapidly attenuated by counter-regulatory desensitization mechanisms. These goals will be accomplished by: 1) cloning, expressing and characterizing the one pharmacologically defined alpha1-adrenergic receptor which has thus far not been cloned (alpha1A). Its signalling properties will be compared with those of the three other cloned alpha1-adrenergic receptors. 2) Developing novel approaches to interdicting the signalling mediated via alpha-adrenergic receptors which may serve as the basis for subsequent design of novel alpha-adrenergic antagonists. 3) Elucidating the nature and consequences of the phosphorylation reactions which regulate the factions of the different alpha-adrenergic receptor subtypes. By producing new information bout the fundamental processes by which the alpha- adrenergic receptors ar activated and desensitized this research should provide the molecular underpinning for the design of drugs and novel strategies to enhance our ability to manipulate cardiovascular alpha- adrenergic receptor signalling mechanisms for therapeutic benefit in human illnesses such as congestive heart failure and hypertension.
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