Storto Marianna, Capobianco Loredana, Battaglia Giuseppe, Molinaro Gemma, Gradini Roberto, Riozzi Barbara, Di Mambro Alessandra, Mitchell Kathryn J, Bruno Valeria, Vairetti Maria P, Rutter Guy A, Nicoletti Ferdinando
I.N.M. Neuromed, Pozzilli, Italy.
Mol Pharmacol. 2006 Apr;69(4):1234-41. doi: 10.1124/mol.105.018390. Epub 2006 Jan 19.
Recent evidence suggests that metabotropic glutamate (mGlu) receptors are involved in the regulation of hormone secretion in the endocrine pancreas. We report here that endogenous activation of mGlu5 receptors is required for an optimal insulin response to glucose both in clonal beta-cells and in mice. In clonal beta-cells, mGlu5 receptors were expressed at the cell surface and were also found in purified insulin-containing granules. These cells did not respond to a battery of mGlu5 receptor agonists that act extracellularly, but instead responded to a cell-permeant analog of glutamate with an increase in [Ca2+]i and insulin secretion. Both effects were largely attenuated by the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). MPEP and its structural analog, (E)-2-methyl-6-styryl-pyridine (SIB-1893), reduced the increase in [Ca2+]i and insulin secretion induced by glucose in clonal beta-cells, whereas a mGlu1 receptor antagonist was inactive. mGlu5 knockout mice showed a defective insulin response at all times after a glucose pulse (1.5 g/kg, i.p.), whereas wild-type mice treated with MPEP (10 mg/kg, i.p.) showed a selective impairment in the late phase of insulin secretion in response to glucose challenge. Mice injected with MPEP or lacking mGlu5 receptors also showed a blunted glucagon response to an insulin challenge. We conclude that insulin secretion is under the control of mGlu5 receptors both in clonal beta-cells and in vivo. Drugs that modulate the function of mGlu5 receptors might affect glucose homeostasis by altering the secretion of pancreatic hormones.
近期证据表明，代谢型谷氨酸（mGlu）受体参与内分泌胰腺中激素分泌的调节。我们在此报告，无论是在克隆β细胞还是在小鼠中，mGlu5受体的内源性激活对于葡萄糖刺激下的最佳胰岛素反应都是必需的。在克隆β细胞中，mGlu5受体表达于细胞表面，也存在于纯化的含胰岛素颗粒中。这些细胞对一系列作用于细胞外的mGlu5受体激动剂无反应，但对一种可透过细胞的谷氨酸类似物有反应，细胞内钙离子浓度（[Ca2+]i）升高且胰岛素分泌增加。这两种效应在很大程度上被mGlu5受体拮抗剂2-甲基-6-（苯乙炔基）吡啶（MPEP）减弱。MPEP及其结构类似物（E）-2-甲基-6-苯乙烯基吡啶（SIB-1893）可降低克隆β细胞中葡萄糖诱导的[Ca2+]i升高和胰岛素分泌，而mGlu1受体拮抗剂则无此作用。mGlu5基因敲除小鼠在腹腔注射葡萄糖脉冲（1.5 g/kg）后的任何时间都表现出胰岛素反应缺陷；而腹腔注射MPEP（10 mg/kg）的野生型小鼠在葡萄糖刺激后的胰岛素分泌后期出现选择性受损。注射MPEP或缺乏mGlu5受体的小鼠对胰岛素刺激的胰高血糖素反应也减弱。我们得出结论，无论是在克隆β细胞还是在体内，胰岛素分泌都受mGlu5受体的控制。调节mGlu5受体功能的药物可能通过改变胰腺激素分泌来影响葡萄糖稳态。
