The PDZ binding motif of the β1 adrenergic receptor modulates receptor trafficking and signaling in cardiac myocytes

Yang Kevin Xiang, Eric Devic, Brian Kobilka

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

β1 and β2 adrenergic receptors (AR) regulate the intrinsic contraction rate in neonatal mouse cardiac myocytes through distinct signaling pathways. It has been shown that stimulation of β1ARs leads to a protein kinase A-dependent increase in contraction rate. In contrast, stimulation of β2ARs has a biphasic effect on contraction rate, with an initial protein kinase A-independent increase followed by a sustained decrease that is blocked by pertussis toxin. The β2AR undergoes agonist-induced endocytosis in cardiac myocytes while the β1AR remains on the cell surface. It has been shown that a PDZ domain binding motif at the carboxyl terminus of β1AR interacts with the postsynaptic density protein PSD-95 when both are expressed in HEK293 cells. We found that mutation of this PDZ binding motif in the β1AR (β1AR-PDZ) enabled agonist-induced internalization in cardiac myocytes. Moreover, stimulation of β1AR-PDZ had a biphasic effect on the myocyte contraction rate similar to that observed following stimulation of the β2AR. The secondary decrease in the contraction rate was mediated by Gi and could be blocked by pertussis toxin. Furthermore, a non-selective endocytosis inhibitor, concanavalin A, inhibited the internalization of wild type β2AR and the mutated β1AR-PDZ, and blocked the coupling of both receptors to Gi. Finally, treating myocytes with a membrane-permeable peptide representing β1AR PDZ motif caused the endogenous β1AR to behave like β1AR-PDZ. These studies suggest that association of the β1AR with PSD-95 or a related protein dictates signaling specificity by retaining the receptor at the cell surface and preventing interaction with Gi.

Original languageEnglish (US)
Pages (from-to)33783-33790
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number37
DOIs
StatePublished - Sep 13 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'The PDZ binding motif of the β<sub>1</sub> adrenergic receptor modulates receptor trafficking and signaling in cardiac myocytes'. Together they form a unique fingerprint.

  • Cite this