β1-adrenergic receptor N-terminal cleavage by ADAM17; the mechanism for redox-dependent downregulation of cardiomyocyte β1-adrenergic receptors

Jing Zhu, Susan F. Steinberg

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

β1-adrenergic receptors (β1ARs) are the principle mediators of catecholamine action in cardiomyocytes. We previously showed that the β1AR extracellular N-terminus is a target for post-translational modifications that impact on signaling responses. Specifically, we showed that the β1AR N-terminus carries O-glycan modifications at Ser37/Ser41, that O-glycosylation prevents β1AR N-terminal cleavage, and that N-terminal truncation influences β1AR signaling to downstream effectors. However, the site(s) and mechanism for β1AR N-terminal cleavage in cells was not identified. This study shows that β1ARs are expressed in cardiomyocytes and other cells types as both full-length and N-terminally truncated species and that the truncated β1AR species is formed as a result of an O-glycan regulated N-terminal cleavage by ADAM17 at R31↓L32. We identify Ser41 as the major O-glycosylation site on the β1AR N-terminus and show that an O-glycan modification at Ser41 prevents ADAM17-dependent cleavage of the β1-AR N-terminus at S41↓L42, a second N-terminal cleavage site adjacent to this O-glycan modification (and it attenuates β1-AR N-terminal cleavage at R31↓L32). We previously reported that oxidative stress leads to a decrease in β1AR expression and catecholamine responsiveness in cardiomyocytes. This study shows that redox-inactivation of cardiomyocyte β1ARs is via a mechanism involving N-terminal truncation at R31↓L32 by ADAM17. In keeping with the previous observation that N-terminally truncated β1ARs constitutively activate an AKT pathway that affords protection against doxorubicin-dependent apoptosis, overexpression of a cleavage resistant β1AR mutant exacerbates doxorubicin-dependent apoptosis. These studies identify the β1AR N-terminus as a structural determinant of β1AR responses that can be targeted for therapeutic advantage.

Original languageEnglish (US)
Pages (from-to)70-79
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume154
DOIs
StatePublished - May 2021
Externally publishedYes

Keywords

  • ADAM17
  • Cardiomyocytes
  • Glycosylation
  • Oxidant stress
  • β-Adrenergic receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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