Stimulation of the beta2-adrenergic receptor (beta2AR) by adrenaline or noradrenaline leads to alterations in the metabolism, excitability, differentiation and growth of many cell types. These effects have traditionally been thought to be mediated exclusively by beta2AR activation of intracellular G proteins. However, it has recently been found that beta2AR regulation of cellular Na+/H+ exchange in some cells involves agonist-promoted coupling of the beta2AR to an intracellular protein called the Na+/H+ exchanger regulatory factor (NHERF). The mechanisms and potential generality of this NHERF-mediated signaling by the beta2AR are unknown. This project aims to elucidate the molecular mechanisms by which the beta2AR can regulate Na+/H+ exchange via association with NHERF, and also aims to find out whether the beta2AR can regulate physiological processes other than Na+/H+ exchange in a NHERF-mediated fashion. Since NHERF seems to act as either an allosteric regulatory protein or adaptor protein, the ability of the beta2AR to regulate the set of intracellular proteins bound by NHERF will be examined. The ability of the beta2AR to regulate the activity of another NHERF binding partner, the platelet-derived growth factor receptor, will also be studied, as will the capacity of NHERF to alter cell growth and proliferation in a beta2AR-regulated fashion. The phosphorylation of NHERF by G protein-coupled receptor kinase 6A, and possibly by other kinases, will also be examined, since an understanding of the regulation of NHERF by phosphorylation may be required for an understanding of NHERF-mediated signaling by the beta2AR. These studies will provide insight into hovel signaling pathways activated by the beta2AR, a receptor that is a common target for therapeutics used in the treatment of hypertension, heart disease and other disorders.
