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J. Biol. Chem., Vol. 279, Issue 27, 28756-28765, July 2, 2004

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Hetero-oligomerization between ₂- and ₃-Adrenergic Receptors Generates a -Adrenergic Signaling Unit with Distinct Functional Properties^*

Andreas Breit, Monique Lagacé, and Michel Bouvier, Holds a Canada Research Chair in Signal Transduction and Molecular Pharmacology

From the Département de Biochimie et Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Montréal, Québec H3C 3J7, Canada

The ability of the closely related ₂- and ₃-adrenergic receptors (AR) to form hetero-oligomers was assessed by bioluminescence resonance energy transfer. Quantitative bioluminescence resonance energy transfer titration curves revealed that the ₂AR has identical propensity to hetero-oligomerize with the ₃AR than to form homo-oligomers. To determine the influence of heterooligomerization, a HEK293 cell line stably expressing an excess of ₃AR over ₂AR was generated so that all ₂AR are engaged in hetero-oligomerization with ₃AR, providing a tool to study the effect of hetero-oligomerization on ₂AR function in the absence of any ₂AR homooligomer. The hetero-oligomerization had no effect on the ligand binding properties of various ₂AR ligands and did not affect the potency of isoproterenol to stimulate adenylyl cyclase. Despite the unaltered ligand binding properties of the _2/3AR hetero-oligomer, the stable association of the ₂AR with the ₃AR completely blocked agonist-stimulated internalization of the ₂AR. Given that the ₃AR is resistant to agonist-promoted endocytosis, the results indicate that the ₃AR acted as a dominant negative of the ₂AR endocytosis process. Consistent with this notion, the _2/3AR hetero-oligomer displayed a lower propensity to recruit -arrestin-2 than the ₂AR. The hetero-oligomerization also led to a change in G protein coupling selectivity. Indeed, in contrast to ₂AR and ₃AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G_s and G_i/o, no G_i/o coupling was observed for the _2/3AR hetero-oligomer. Together, these results demonstrate that hetero-oligomerization between ₂AR and ₃AR forms a -adrenergic signaling unit that possesses unique functional properties.

Received for publication, December 5, 2003 , and in revised form, April 6, 2004.

^* This work was supported in part by grants from the Canadian Institute for Health Research and from the Heart and Stroke Foundation of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a post-doctoral fellowship from AstraZeneca (Montréal).

To whom correspondence should be addressed. Tel.: 514-343-6372; Fax: 514-343-2210; E-mail: michel.bouvier{at}umontreal.ca.

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