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

Abstract

Many metabolic factors affect the secretion of insulin from ␤-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 ␤-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 glutamatedependent 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 ␣-cells. These results indicate that L-glutamate triggers somatostatin secretion from ␦-cells by way of the GluR4c-flip receptor under lowglucose conditions. The released somatostatin may complete the feedback inhibition of ␣-cells. Thus, ␣-and ␦-cells may communicate with each other through Lglutamate and somatostatin signaling.

Function and expression of somatostatin receptors of the endocrine pancreas

“…This theory is supported by the recent finding that glucagon together with Lglutamate, an amino-acid which is co-secreted from pancreatic A-cells, can together stimulate pancreatic SST secretion at low glucose (Muroyama et al, 2004). Also an activation of beta-adrenergic system by hypoglycemia may also lead to increased secretion of SST (Kanatsuka et al, 1981;Hermansen 1980).…”

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

“…Islet cells express functional glutamate receptors (9 -12) and vesicular glutamate transporters (13), suggesting that glutamate is a crucial intercellular signal mediator. Glutamate is co-secreted with glucagon, and acute stimulation of its receptors modulates the secretion of glucagon, insulin, and somatostatin (8, 14 -19).…”

Exocytosis of D-Aspartate from INS-1E Clonal .BETA. Cells

“…13,15) a cells also receive L-glutamate signals by way of a metabotropic glutamate receptor, which causes inhibition of glucagon secretion. 16) Thus, the present study suggests the possibility that D-aspartate also participates in the L-glutamate-mediated intercellular-or intracellular signaling network in islets. In fact, our preliminary experiment indicated that D-aspartate inhibits glucagon secretion, supporting this possibility (Iharada and Moriyama, unpublished observation).…”

“…In addition, the KCl-dependent secretion Recent increasing evidence shows that excitatory amino acids are involved in the regulation of hormonal secretion in islets. 15) Islets of Langerhans use L-glutamate as a primary intercellular messenger to regulate the secretion of glucagon, followed by regulation of blood glucose [15][16][17] : L-glutamate is stored in glucagon-containing secretory granules in a cells and co-secreted with glucagon upon low glucose stimulation. L-Glutamate is also present in pancreatic polypeptide-containing secretory granules in a subpopulation of F cells.…”