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J. Biol. Chem., Vol. 282, Issue 26, 19042-19051, June 29, 2007

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Specificity of Olfactory Receptor Interactions with Other G Protein-coupled Receptors^*

Cristina F. Bush, Seth V. Jones^¶, Alicia N. Lyle^||, Kenneth P. Minneman, Kerry J. Ressler^¶, and Randy A. Hall¹

From the Departments of Pharmacology and Psychiatry, the ^||Division of Cardiology, and the ^¶Yerkes National Primate Center, Emory University School of Medicine, Atlanta, Georgia 30322

Studies on olfactory receptor (OR) pharmacology have been hindered by the poor plasma membrane localization of most ORs in heterologous cells. We previously reported that association with the ₂-adrenergic receptor (₂-AR) facilitates functional expression of the OR M71 at the plasma membrane of HEK-293 cells. In the present study, we examined the specificity of M71 interactions with other G protein-coupled receptors (GPCRs). M71 was co-expressed in HEK-293 cells with 42 distinct GPCRs, and the vast majority of these receptors had no significant effect on M71 surface expression. However, co-expression with three subtypes of purinergic receptor (P2Y₁R, P2Y₂R, and A_2AR) resulted in markedly enhanced plasma membrane localization of M71. Agonist stimulation of M71 co-expressed with P2Y₁R and P2Y₂R activated the mitogen-activated protein kinase pathway via coupling of M71 to G_o. We also examined the ability of ₂-AR, P2Y₁R, P2Y₂R, and A_2ARto interact with and regulate ORs beyond M71. We found that co-expression of ₂-AR or the purinergic receptors enhanced the surface expression for an M71 subfamily member but not for several other ORs from different subfamilies. In addition, through chimeric receptor studies, we determined that the second transmembrane domain of ₂-AR is necessary for ₂-AR facilitation of M71 plasma membrane localization. These studies shed light on the specificity of OR interactions with other GPCRs and the mechanisms governing olfactory receptor trafficking.

Received for publication, November 21, 2006 , and in revised form, April 25, 2007.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-727-3699; Fax: 404-727-0365; E-mail: rhall{at}pharm.emory.edu.

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