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

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

Many metabolic factors affect the secretion of insulin from ß-cells and glucagon from -cells of the islets of Langerhans to regulate blood glucose. Somatostatin from -cells, considered a local inhibitor of islet function, reduces insulin and glucagon secretion by activating somatostatin receptors in islet cells. Somatostatin secretion from -cells is increased by high glucose via glucose metabolism in a similar way to insulin secretion from ß-cells. However, it is unknown how low glucose triggers somatostatin secretion. Because L-glutamate is cosecreted with glucagon from -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 -cells express GluR4c-flip, a newly identified splicing variant of GluR4, an (RS)--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 Ca²⁺ dependent and blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. Somatostatin in turn inhibited the secretion of L-glutamate and glucagon from -cells. These results indicate that L-glutamate triggers somatostatin secretion from -cells by way of the GluR4c-flip receptor under low-glucose conditions. The released somatostatin may complete the feedback inhibition of -cells. Thus, - and -cells may communicate with each other through L-glutamate and somatostatin signaling.

Abbreviations: AM, acetoxymethylester; AMPA, (RS)--amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; GABA, -aminobutyric acid; GST, glutathione S-transferase; iGluR, ionotropic glutamate receptor; mGluR, metabotropic glutamate receptor; mGluR4, metabotropic glutamate receptor type 4; NMDA, N-methyl-D-aspartate; SSTR, somatostatin receptor

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