Norepinephrine (NE) and epinephrine (EPI) act through alpha and beta-adrenergic receptors (AR) subtypes coupled to hetero-trimeric G proteins to control the circulation. Several important mechanisms regulating receptor function involve phosphorylation by PKA, PKC or GRKs such as betaARK. Phosphorylation promotes binding of beta-arrestin to the receptors leading to their desensitization. Abnormal function of these regulatory mechanisms may contribute to cardiomyopathy and congestive heart failure. Recent evidence suggests that several aspects of signaling by beta-ARs and other GPCRs are not readily explainable by their effects on second messengers, including activation of MAP kinase cascades. This proposal has three aims which focus on elucidating novel mechanisms regulating signaling through beta-ARs and other GPCRs, targeting the receptors, the kinases which phosphorylate them, and the beta-arrestins which bind to them. The goals are to elucidate 1) how the receptors activate mitogenic and other signaling pathways by novel mechanisms, forming complexes with receptor tyrosine kinases and SH3 domain containing proteins; 2) novel ways in which PKA and GRKs regulate receptor function. The physiology of GRK action will be probed in vivo with knockout animals; 3) new roles for beta-arrestins in regulation and signaling. Novel interactions of beta-arrestin with the kinases cSrc, JNK3 and ASK as well as with other binding partners will be investigated and the physiology of beta-arrestin explored with knockout animals. Understanding of the regulation of beta-ARs may point toward novel therapeutic strategies for cardiovascular diseases.
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