title: Activation of islet 5-HT4 receptor regulates glycemic control through promoting insulin secretion.
abstract: Mosapride, a gastrointestinal prokinetic drug, is an agonist of 5-hydroxytryptamine (5-HT) receptor 4 that also reduces blood glucose. Whether 5-HT4 receptor is distributed in pancreatic islets and whether mosapride can directly stimulate insulin secretion is unclear. In the present study, the protein expression and cellular location of 5-HT4 receptor in pancreas was detected through western blotting and immunofluorescence. The acute effects of 5-HT4 receptor agonists, mosapride and prucalopride, on insulin secretion were investigated in vivo and in vitro in normal and alloxan-induced diabetes rats. The results indicated that 5-HT4 receptor immunoreactivity was co-existed in the islets insulin-immunoreactive cells of rat, mouse, pig and human. However the immunoreactive cells of insulin and 5-HT4 receptor and the protein expression of 5-HT4 receptor were significantly decreased in the pancreas of alloxan-induced diabetes rats. In normal rats, mosapride and prucalopride decreased blood glucose and increased insulin secretion during glucose tolerance test, in association with an increase in glucose-stimulated insulin secretion, which was abolished by the 5-HT4 receptor antagonist GR113808. In diabetes rats, mosapride and prucalopride failed to improve blood glucose and insulin levels in the group of 180mg/kg alloxan, but increased glucose-stimulated insulin secretion in the group of 120mg/kg alloxan in vitro. We conclude that 5-HT4 receptor is distributed in the islet β cell. Activation of 5-HT4 receptor is able to stimulate insulin secretion directly, thereby reduce blood glucose. The study provides important experimental evidences for the 5-HT4 receptor regulating insulin secretion and acting as a potential drug target in diabetes treatment.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: chenhui0429@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: hongfengshengli@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: 5117149cy@sina.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: 0925liji@sina.com.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: hylyyys@163.com.
authors.forename: Yuan-Sheng
authors.initials: YS
authors.lastname: Yao
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: rebecca@ccmu.edu.cn.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: 13581582937@163.com.
authors.forename: Li-Fei
authors.initials: LF
authors.lastname: Zheng
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing, China. Electronic address: zhu_jx@ccmu.edu.cn.
authors.forename: Jin-Xia
authors.initials: JX
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4
keywords: 5-HT(4) receptor; Blood glucose; GR113808 (PubChem CID: 119376); Insulin; Islet β cells; Mosapride; Mosapride citrate (PubChem CID: 119583); Prucalopride; Prucalopride succinate (PubChem CID: 9870009)