Heterodimerization of beta1- and beta2-adrenergic receptor subtypes optimizes beta-adrenergic modulation of cardiac contractility.
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 beta-adrenergic receptor (betaAR) subtypes expressed in the heart, beta1AR, and beta2AR, and its physiological relevance. In intact adult-mouse cardiac myocytes lacking native beta1AR and beta2AR, coexpression of both betaAR 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 betaAR agonist stimulation with isoproterenol (ISO) was shifted leftward by approximately 1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of betaAR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of beta1AR greatly suppressed ligand-independent spontaneous activity of coexisting beta2ARs. Thus, heterodimerization of beta1AR and beta2AR in intact cardiac myocytes creates a novel population of betaARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing beta-adrenergic modulation of cardiac contractility.
Zhu
Wei-Zhong
WZ
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA.
Chakir
Khalid
K
Zhang
Shengjun
S
Yang
Dongmei
D
Lavoie
Catherine
C
Bouvier
Michel
M
Hébert
Terence E
TE
Lakatta
Edward G
EG
Cheng
Heping
H
Xiao
Rui-Ping
RP
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D019281:Dimerization; D047468:Immunoprecipitation; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000737:chemistry; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis / Q000737:chemistry* / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000737:chemistry* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D008024:Ligands; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP