| Budget Amount *help |
¥3,760,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Background and Aims: Motilin is an important endogenous regulator of gastrointestinal motor function, mediated by the class I G protein-coupled motilin receptor Motilin and erythromycin, two chemically distinct full agonists of the motilin receptor, are known to bind to distinct regions of this receptor, based on previous systematic mutagenesis of extracellular regions that dissociated the effects on these two agents. While there has been dysmotility of GI tract in patients with diabetes mellitus, roles of this receptor is not yet clear. In the current work, we have examined the predicted intracellular loop domains of this receptor for effects on motilin- and erythromycin-stimulated activity, and explored the distribution of this receptor along the GI tract in diabetic patients. Methods: We have studied sequential deletions of residues within the predicted first, second, and third intracellular loop domains of the motilin receptor and have utilized alanine, phenylalanine, and histidine
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replacement fur each residue within functionally important segments. Post-mortem and surgical human tissue specimens with no hemorrhage, necrosis, or tumor were obtained from lower esophagus, stomach, duodenum, jejunum, ileum, colon, and rectum in subjects with and without diabetes mellitus. We analyzed expression of mRNA and immunoreactivity of motilin and GHS receptors. Results: Tyr66, Arg136, and Val299 were critical on motilin and erythromycin biological activity. These data suggested that action by different chemical classes of agonists likely yield a common activation state of the cytosolic face of this receptor that is responsible for interaction with its G protein. In diabetic patients, motilin receptor was expressed 10 to 100 times more in the muscle layer than in mucosal layer, similar to non-diabetic subjects. These data suggested that motilin agonists such as peptide motilide and non-peptidyl erythromycin and ghrelin agonists may be useful drugs for dysmotility of GI tract in diabetic patients. Less
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