N-Tertaining a New Signaling Paradigm for the Cardiomyocyte β1-Adrenergic Receptor

beta(1)-adrenergic receptors (beta(1)ARs) are the principle mediators of catecholamine actions in cardiomyocytes. beta(1)ARs rapidly adjust cardiac output and provide short-term hemodynamic support for the failing heart by activating a Gs-adenylyl cyclase pathway that increases 3'-5'-cyclic adenosine monophosphate and leads to the activation of protein kinase A and the phosphorylation of substrates involved in excitation-contraction coupling. However, chronic persistent beta(1)AR 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 beta(1)AR-driven maladaptive responses remains uncertain because chronic persistent beta(1)AR 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 beta(1)ARs signal exclusively as full-length receptor proteins. Our recent studies show that beta(1)ARs 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 beta(1)AR N-terminus, and that N-terminally truncated beta(1)ARs remain signaling competent, but their signaling properties differ from those of the full-length beta(1)AR. The N-terminally truncated form of the beta(1)AR constitutively activates the protein kinase B signaling pathway and confers protection against doxorubicin-dependent apoptosis in cardiomyocytes. These studies identify a novel signaling paradigm for the beta(1)AR, implicating the N-terminus as a heretofore-unrecognized structural determinant of beta(1)AR responsiveness that could be pharmacologically targeted for therapeutic advantage.