N-TERTAINING A NEW SIGNALING PARADIGM FOR THE CARDIOMYOCYTE β1-ADRENERGIC RECEPTOR.

β1-adrenergic receptors (β1ARs) are the principle mediators of catecholamine actions in cardiomyocytes. β1ARs rapidly adjust cardiac output and provide short-term hemodynamic support for the failing heart by activating a Gs-adenylyl cyclase pathway that increases cAMP and leads to the activation of protein kinase A and the phosphorylation of substrates involved in excitation-contraction coupling. However, chronic persistent β1AR activation in the setting of heart failure leads to a spectrum of maladaptive changes that contribute to the evolution of heart failure. The molecular basis for β1AR-driven maladaptive responses remains uncertain, since chronic persistent β1AR activation has been linked to the activation of both proapoptotic and antiapoptotic signaling pathways. Of note, studies to date have been predicated on the assumption that β1ARs signal exclusively as full-length receptor proteins. Our recent studies show that β1ARs are detected as both full-length and N-terminally truncated species in cardiomyocytes, that N-terminal cleavage is regulated by O-glycan modifications at specific sites on the β1AR N-terminus, and that N-terminally truncated β1ARs remain signaling competent, but their signaling properties differ from those of the full-length β1AR. The N-terminally truncated form of the β1AR constitutively activates the AKT signaling pathway and confers protection against doxorubicin-dependent apoptosis in cardiomyocytes. These studies identify a novel signaling paradigm for the β1AR, implicating the N-terminus as a heretofore-unrecognized structural determinant of β1AR responsiveness that could be pharmacologically targeted for therapeutic advantage.