This is a request for years 05-9 of a project designed to further our understanding of the molecular and biochemical mechanisms of signal transduction and physiology mediated by alpha1-adrenergic receptor (AR) subtypes. Alpha1-ARs (a1A, a1B and a1D) are members of the G-protein-coupled receptor family of proteins that mediate the sympathetic nervous system by binding the endogenous catecholamines, epinephrine and norepinephrine. These receptors are a current therapeutic target in the management of hypertension, benign prostatic hypertrophy, and urinary incontinence through their role in smooth muscle contraction. Alterations in the signaling pathways and/or receptors themselves may contribute to the pathogenesis of these diseases. Thus, a detailed understanding of the structure-function of these receptors and their signal transduction mechanisms will be crucial to our understanding of the pathology and treatment of these diseases. The current state of knowledge in alpha1-AR subtype pharmacology (i.e. localization, signaling differences and pathology) are impaired due to the lack of specific antibodies, agonists and antagonists that have enough selectivity to prevent cross-binding among the subtypes. In past grants, our laboratory has made significant contributions to the structure-function of alpha1-AR subtypes by characterizing determinants in the binding pocket that contribute to agonist and antagonist binding and to subtype selectivity. We have also developed transgenic mice that systemically overexpress the alpha1B-AR subtype and showed that it causes neurological as well as cardiovascular pathology. Significant progress has been made in the current funding period and this application builds upon these observations. Based on these results, we now propose to determine how similar or different the alpha1-AR subtypes control various aspects of their function. This application integrates molecular and cellular methodologies with state of the art in vitro and in vivo approaches in an comprehensive experimental design that will significantly increase our understanding of the subtype-specific binding pocket, the localization, signaling and functional differences between alpha1-subtypes that will enhance our knowledge of drug design and therapeutic strategies. ? ? ?
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