N-Tertaining a New Signaling Paradigm for the Cardiomyocyte β 1 -Adrenergic Receptor.

Susan F Steinberg

Journal of cardiovascular pharmacology 2022 Sep 01

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β 1 -adrenergic receptors (β 1 ARs) are the principle mediators of catecholamine actions in cardiomyocytes. β 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 β 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 β 1 AR-driven maladaptive responses remains uncertain because chronic persistent β 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 β 1 ARs signal exclusively as full-length receptor proteins. Our recent studies show that β 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 β 1 AR N-terminus, and that N-terminally truncated β 1 ARs remain signaling competent, but their signaling properties differ from those of the full-length β 1 AR. The N-terminally truncated form of the β 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 β 1 AR, implicating the N-terminus as a heretofore-unrecognized structural determinant of β 1 AR responsiveness that could be pharmacologically targeted for therapeutic advantage. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Citation

Susan F Steinberg. N-Tertaining a New Signaling Paradigm for the Cardiomyocyte β 1 -Adrenergic Receptor. Journal of cardiovascular pharmacology. 2022 Sep 01;80(3):328-333