Regulation of GPCR function by oligomerization

G蛋白偶联受体(GPCR)对多种细胞功能具有重要作用。它是神经传递或药物作用的目标。长期以来，GPCR一直被认为是与多种G蛋白偶联的单体。近年来，GPCRs之间的寡聚体已被报道，如GABA_B受体、肾上腺素能受体和多巴胺受体。由于GPCR寡聚可以改变信号转位或细胞转位，因此GPCR寡聚体的形成作为一种新的GPCR化机制备受关注。在这里，我们研究了G蛋白偶联的嘌呤能受体的寡聚化，它们被分为4个腺苷受体(A_1，A_1，A_1；2B&gt；，A_3)和8个P2Y受体(1，2，4，6，11，12，13，14)，它们对神经传递具有负性调节作用。得到了以下结果。(1)腺苷受体A_1和A_1、A_1/P_Y_2、A_1/P_Y_1、A_1/P_Y_2、A_1/P_Y_2、A_1/P_Y_2和A_1/P_Y_2。…观察这是一种直接观察A_1和P_2Y_2受体在转基因培养细胞和自然组织中构成表达的低聚体形成的有效方法。(2)A_1腺苷受体和P_2Y_2受体共转染HEK293T细胞后，细胞信号转导发生明显改变。同时加入A_1R和P_2Y_2R激动剂后，A_1R和P_2Y_2R激动剂对腺苷环化酶的抑制作用减弱。在共表达细胞中同时加入A_1R激动剂，可协同增强G_&lt；Q/11&gt；P2Y_2R引起的细胞内Ca~(2+)水平的升高。这些结果表明，A_1R和P2Y_2R的寡聚产生了一个独特的复合体，其中两个受体的同时激活引起了结构的改变，干扰了通过G&lt；I/o&gt；而通过G&lt；q/11&gt；的信号转导。(3)嘌呤能受体间寡聚体的形成在腺苷/三磷酸腺苷对细胞功能的调节中起重要作用。较少

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