| Co-Investigator(Kenkyū-buntansha) |
UEZONO Yasuhito Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (20213340)
HAYASHI Hideki Nagasaki University, Graduate School of Biomedical Sciences, Lecturer, 大学院・医歯薬学総合研究科, 講師 (10218589)
貝原 宗重 長崎大学, 大学院・医歯薬学総合研究科, (前)助教授 (40274633)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
GABAergic enteric neurons and GABA receptors, GABA-A receptor (GAR) and heterodimeric GABA-B receptor (GBR), are present in the intestine. In vivo studies with microdialysis using dog intestine identified that GBR operated predominantly relatively to GAR in the physiological intestinal motility associated with acetylcholine release. The functional GABA_B receptors (GBR) form heterodimer composed of the two different proteins, GABA_<B1> (GB_1R) and GABA_<B2> (GB_2R) subunits. The GB_1R is necessary for agonist binding and the GB_2R activates the downstream of G protein-coupled signaling systems. There have been cloned seven subunits of splice variants of GB_1R, from GB_<1a>R to GB_<1g>R, and only one GB_2R type. RT-PCR revealed that mRNAs of GB_1R, from GB_<1a>R to GB_<1g>R, except GB_<1e>R were present in the human and dog intestine. The functional GBR was detected to form a heterodimer composed of GB_<1a>R and GB_2R, but not to GB_<1a>R alone and GB_2R alone using confocal imaging and fluorescence resonance energy transfer (FRET) analysis of the baby hamster kidney (BHK) cell and the Xenopus oocyte expression systems. In Xenopus oocytes coexpressing each GB_<1a>R, GB_<1b>R, GB_<1c>R or GB_<1d>R together with GB_2R, the potency of responses to baclofen, a GBR agonist was GB_<1a>R=GB_<1b>R>GB_<1c>R>>GB_<1d>R. Heterodimeric GBR was detected to be also present also in the lower esophageal sphincter, and it was located on the neuronal cell membranes, thereby indicating that a GBR agonist, baclofen used for treatment of reflux disease
Thus, GBR agonists and antagonists may be useful for treatment of gut motility disorders. The distribution and function of GBR may vary with the different isoforms of GB_1R, therefore research of substances targeting GB_1R may be useful for development of organ-specific drugs in the intestine.
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