| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Tokiko Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Staff Scientist, 東京都神経科学総合研究所, 研究員 (10415531)
TSUGA Hirofumi Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute for Neuroscience, Staff Scientist, 東京都神経科学総合研究所, 研究員 (00374158)
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| Budget Amount *help |
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2004: ¥11,000,000 (Direct Cost: ¥11,000,000)
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| Research Abstract |
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
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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
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