Heterodimerization of β1- and β2-adrenergic receptor subtypes optimizes β-adrenergic modulation of cardiac contractility

Wei Zhong Zhu, Khalid Chakir, Shengjun Zhang, Dongmei Yang, Catherine Lavoie, Michel Bouvier, Terence E. Hébert, Edward G. Lakatta, Heping Cheng, Rui Ping Xiao

Research output: Contribution to journalArticlepeer-review

Abstract

Intermolecular interactions between members of both similar and divergent G protein-coupled receptor subfamilies have been shown in various experimental systems. Here, we demonstrate heterodimerization of predominant β-adrenergic receptor (βAR) subtypes expressed in the heart, β1AR, and β2AR, and its physiological relevance. In intact adult-mouse cardiac myocytes lacking native β1AR and β2AR, coexpression of both βAR subtypes led to receptor heterodimerization, as evidenced by their coimmunoprecipitation, colocalization at optical resolution, and markedly increased binding affinity for subtype-selective ligands. As a result, the dose-response curve of myocyte contraction to βAR agonist stimulation with isoproterenol (ISO) was shifted leftward by ≈1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of βAR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of β1AR greatly suppressed ligand-independent spontaneous activity of coexisting β2ARs. Thus, heterodimerization of β1AR and β2AR in intact cardiac myocytes creates a novel population of βARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing β-adrenergic modulation of cardiac contractility.

Original languageEnglish (US)
Pages (from-to)244-251
Number of pages8
JournalCirculation research
Volume97
Issue number3
DOIs
StatePublished - Aug 5 2005
Externally publishedYes

Keywords

  • Cardiac contractility
  • G protein-coupled receptors
  • Ligand binding
  • Receptor dimerization
  • β-adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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