| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
Background. Motilin and ghrelin have been recognized as important endogenous regulators of gastrointestinal (GI) motor function in mammals, mediated by the motilin receptor and by the closely-related growth hormone secretagogue (GHS) receptor, respectively. The aims of this study were to identify the ligand-binding sites within the human motilin receptor, and to explore the distribution of motilin and GHS receptors along the human gastrointestinal tract, and to establish the molecular nature of the human motilin receptor. Methods. We examined the extracellular domains of the human motilin receptor using the methods of receptor mutagenesis and photoaffinity labeling. We also analyzed levels of expression of mRNA and immunoreactivity for motilin and GHS receptors in the human GI tract. Results. Cys residues in the amino terminus and the first and second extracellular loop domains in the motilin receptor, Cys25, Cys30, Cys111, and Cys235, are critical for both peptide ligand, motilin, and non-peptidyl ligand, erythromycin, biological activities, conserving the disulfide bond in this receptor. The perimembranous residues, Gly36, Pro103, Leu109, and Phe332, are important only for binding and biological activity of peptide ligand. The long form of the motilin receptor, but not the short form, was expressed in all parts of the GI tract, and expressed at higher levels in muscle than in mucosa. Motilin receptor immunoreactivity was present on muscle cells and myenteric plexus. In contrast, GHS receptor mRNA and immunoreactivity were expressed equally in both mucosal and muscle layers in all parts of GI tract. Conclusions. These results, suggest that differential contribution of motilin receptor extracellular domains for peptide ligand and non-peptidyl ligand binding and action, and the diffuse muscle expression of the motilin receptor along the entire GI tract make it a useful potential target for motilide drugs for dysmotility.
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