Impactful findings with reverberating consequences – this is what AJP-Heart and Circ Rapid Reports are here for. Listen as Associate Editor Dr. Jonathan Kirk (Loyola University Chicago Stritch School of Medicine) interviews lead author Dr. Susan Steinberg (Columbia University) and expert Dr. Michael Kapiloff (Stanford University) about this novel work by Zhu and Steinberg. More than 20 years ago, Steinberg and collaborators used immunoblot analysis to implicate compartmentalization as a mechanism that imparts beta-adrenergic receptor subtype signaling specificity. Of note, these studies also provided the unexpected observation that the beta1-adrenergic receptor subtype accumulates as both full-length and N-terminally truncated species; in contrast, beta2-adrenergic receptors are expressed exclusively as a single full-length species. The Steinberg laboratory went on to identify the molecular mechanisms that control the maturational processing of the full-length receptor to an N-terminally truncated form (including the role of a member of the matrix metalloproteinase family of enzymes) and the functional importance of this finding. They showed that full-length and N-terminally truncated beta1-adenergic receptors differ in their signaling phenotype; the N-terminally truncated beta1-adenergic receptor plays a unique role to constitutively activate an AKT signaling pathway that is cardioprotective.
This Rapid Report expands upon the previous studies by showing that the beta1-adrenergic receptor is also cleaved by trypsin, an enzyme used in protocols to isolate cardiomyocytes from ventricular tissue. This finding suggests that studies on cardiomyocytes isolated in this manner should be interpreted with caution. In the broader context, the cleavage mechanism that regulates beta1-adrenergic receptor signaling uncovered by Zhu and Steinberg has important clinical implications given the fact that beta-adrenergic receptors are first-line targets for heart failure (with beta blockers one of the most prescribed medications). The podcast discusses several questions. Are beta1-adrenergic receptors also cleaved (and hence catecholamine responsiveness also altered) by functionally relevant inflammatory proteases in the setting of cardiac injury or myocarditis? Do the full-length and truncated forms of the beta1-adrenergic receptor play distinct roles in the evolution of heart failure? This research clearly is a springboard for future studies. Listen and find out why.
Jing Zhu and Susan F. Steinberg Trypsin cleavage of the beta1-adrenergic receptor Am J Physiol Heart Circ Physiol, published March 1, 2022. DOI: 10.1152/ajpheart.00005.2022