A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From δ-Cells of Islets of Langerhans

A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From δ-Cells of Islets of Langerhans Akiko Muroyama 1 , Shunsuke Uehara 1 , Shouki Yatsushiro 1 , Noriko Echigo 1 , Riyo Morimoto 1 , Mitsuhiro Morita 2 , Mitsuko Hayashi 1 , Akitsugu Yamamoto 3 , Duk-Su Koh 4 and Yoshinori Moriyama 1 1 Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan 2 Tokyo College of Pharmacy, Tokyo, Japan 3 Nagahama Institute of Bioscience and Technology, Shiga, Japan 4 Department of Physics, Pohang University of Science and Technology, Pohang, Republic of Korea Address correspondence and reprint requests to Dr. Yoshinori Moriyama, Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan. E-mail: moriyama{at}pheasant.pharm.okayama-u.ac.jp Abstract Many metabolic factors affect the secretion of insulin from β-cells and glucagon from α-cells of the islets of Langerhans to regulate blood glucose. Somatostatin from δ-cells, considered a local inhibitor of islet function, reduces insulin and glucagon secretion by activating somatostatin receptors in islet cells. Somatostatin secretion from δ-cells is increased by high glucose via glucose metabolism in a similar way to insulin secretion from β-cells. However, it is unknown how low glucose triggers somatostatin secretion. Because l -glutamate is cosecreted with glucagon from α-cells under low-glucose conditions and acts as a primary intercellular messenger, we hypothesized that glutamate signaling triggers the secretion of somatostatin. In this study, we showed that δ-cells express GluR4c-flip, a newly identified splicing variant of GluR4, an (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptor of rat. After treatment with l -glutamate, AMPA, or kainate, secretion of somatostatin from isolated islets was significantly stimulated under low-glucose conditions. The glutamate-dependent somatostatin secretion was Ca 2+ dependent and blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. Somatostatin in turn inhibited the secretion of l -glutamate and glucagon from α-cells. These results indicate that l -glutamate triggers somatostatin secretion from δ-cells by way of the GluR4c-flip receptor under low-glucose conditions. The released somatostatin may complete the feedback inhibition of α-cells. Thus, α- and δ-cells may communicate with each other through l -glutamate and somato