Regulation of GPCR function by oligomerization

点击翻译按钮获取中文摘要

G protein-coupled receptor (GPCR) is important for various cellular functions. It is a target for neurotransmission or drug action. For a long time, GPCR has been considered to work as a monomer coupling with various G proteins. Recently, oligomers between GPCRs have been reported, such as GABA_B receptors, adrenergic receptors and dopamine receptors. Because signaling or cellular translocation can be modified by the GPCR oligomerization, GPCR oligomer formation has attracted much attention as a new mechanism for GPCR function. Here, we studied on the oligomerization of G protein-coupled purinergic receptors which are divided into 4 adenosine receptors (A_1, A_<2A>, A_<2B>, A_3) and 8 P2Y receptors (1, 2, 4, 6, 11, 12, 13, 14), known to regulate neurotransmission negatively. The following results were obtained. (1)A_1 and A_<2A> adenosine receptors were found to associate with P2Y receptors, i.e. A_<2A>/P2Y_1, A_<2A>/P2Y_2, A_1/P2Y_1 and A_1/P2Y_2. Electron microscopic observation was … More revealed to be an efficient method for the direct observation of oligomer formation among A_1 and P2Y_2 receptors in both transfected cultured cells and natural tissues where these receptors constitutively express. (2)Cell signaling in the HEK293T cells cotransfected with A_1 adenosine receptor and P2Y_2 receptor was found to be significantly modified. The functional activity of A_1R, as indicated by the G_<i/o>-mediated inhibition of adenylyl cyclase, in the cotransfected cells was attenuated by the simultaneous addition of A_1R and P2Y_2R agonists. The increase in intracellular Ca^<2+> levels induced by P2Y_2R activation of G_<q/11> was synergistically enhanced by the simultaneous addition of an A_1R agonist in the coexpressing cells. These results suggest that oligomerization of A_1R and P2Y_2R generates a unique complex in which the simultaneous activation of the two receptors induces a structural alteration that interferes signaling via G_<i/o> but enhances signaling via G_<q/11>. (3)From these results, oligomer formation among purinergic receptors was found to be important for the regulation of cell function by adenosine/ATP. Less