Specificity of olfactory receptor interactions with other G protein-coupled receptors

Abstract

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 β2-adrenergic receptor (β2-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 (P2Y 1R, P2Y2R, and A2AR) 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 Gαo. We also examined the ability of β2-AR, P2Y1R, P2Y2R, and A2AR to interact with and regulate ORs beyond M71. We found that coexpression of β2-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 β2-AR is necessary for β2-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. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.