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Regulation of GPCR function by oligomerization

通过寡聚化调节 GPCR 功能

基本信息

批准号：
16300125
负责人：
NAKATA Hiroyasu
金额：
$ 9.73万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

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

G蛋白偶联受体（GPCR）对多种细胞功能都很重要。它是神经传递或药物作用的靶点。长期以来，GPCR一直被认为是作为单体与各种G蛋白偶联而起作用。近年来，GPCR之间的寡聚体被报道，如GABA_B受体、肾上腺素能受体和多巴胺受体。由于GPCR寡聚化可以修饰信号传导或细胞转位，因此GPCR寡聚体形成作为GPCR功能的新机制引起了人们的广泛关注。本实验研究了G蛋白偶联的嘌呤能受体的寡聚化，这些受体被分为4种腺苷受体（A_1，<2A>A_3，A_1<2B>，A_3）和8种P_2Y受体（1，2，4，6，11，12，13，14），已知它们负性调节神经传递。获得了以下结果。(1)A A_1和A_2<2A>腺苷受体与P_2Y受体结合，即<2A>A_1/P_2Y_1、A_1<2A>/P_2Y_2、A_1/P_2Y_1和A_1/P_2Y_2。电子显微镜观察 ...更多信息结果表明，该方法是一种直接观察A_1和P2Y_2受体组成型表达的细胞和自然组织中A_1和P2Y_2受体寡聚体形成的有效方法。（2）A_1腺苷受体和P_2Y_2受体共转染的HEK 293 T细胞的细胞信号转导功能明显改变。同时加入A_1R和P2Y_2R激动剂，可减弱A_1R的功能活性，即G_<i/o>介导的腺苷酸环化酶抑制。在共表达细胞中同时加入A_1 R激动剂可协同增强P2Y_2 R激活G_<q/11>引起的细胞内Ca^<2+>水平的升高。这些结果表明，A_1R和P2Y_2R的寡聚化产生了一个独特的复合物，其中两种受体的同时激活引起了结构的改变，干扰了G_<i/o>信号，但增强了G_<q/11>信号。（3）从这些结果可以看出，嘌呤能受体之间的寡聚体形成对于腺苷/ATP调节细胞功能是重要的。少

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Purinergic receptor complex : generating adenine nucleotide-sensitive adenosine receptors.

嘌呤能受体复合物：产生腺嘌呤核苷酸敏感的腺苷受体。

DOI：
发表时间：
2004
期刊：
Journal of Pharmacological Sciences 94
影响因子：
0
作者：
Yoshioka;K.
通讯作者：
K.

Regulation of pharmacology by hetero-oligomerization between A_1 adenosine receptor and P2Y_2 receptor.

A_1 腺苷受体和 P2Y_2 受体之间异源寡聚化的药理学调节。

DOI：
发表时间：
2006
期刊：
Biochemical Biophysical Research Communication 351
影响因子：
0
作者：
Suzuki;T.
通讯作者：
T.

[Heterogeneity of G protein-coupled receptor generated by post-translational mechanisms and its clinical meanings].

翻译后机制产生的G蛋白偶联受体的异质性及其临床意义

DOI：
发表时间：
2004
期刊：
Nihon yakurigaku zasshi. Folia pharmacologica Japonica
影响因子：
0
作者：
A. Tanoue;T. Koshimizu;G. Tsujimoto;H. Nakata;S. Hirose;Taku Fukuzawa;J. Abe;H. Kurose
通讯作者：
H. Kurose

Clathrin required for phosphorylation and internalization of beta 2-adrenergic receptor by G protein-coupled receptor kinase 2 (GRK2).

G 蛋白偶联受体激酶 2 (GRK2) 磷酸化和内化 β2-肾上腺素受体所需的网格蛋白。