Cabrera Over, Jacques-Silva M Caroline, Speier Stephan, Yang Shao-Nian, Köhler Martin, Fachado Alberto, Vieira Elaine, Zierath Juleen R, Kibbey Richard, Berman Dora M, Kenyon Norma S, Ricordi Camillo, Caicedo Alejandro, Berggren Per-Olof
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Cell Metab. 2008 Jun;7(6):545-54. doi: 10.1016/j.cmet.2008.03.004.
An important feature of glucose homeostasis is the effective release of glucagon from the pancreatic alpha cell. The molecular mechanisms regulating glucagon secretion are still poorly understood. We now demonstrate that human alpha cells express ionotropic glutamate receptors (iGluRs) that are essential for glucagon release. A lowering in glucose concentration results in the release of glutamate from the alpha cell. Glutamate then acts on iGluRs of the AMPA/kainate type, resulting in membrane depolarization, opening of voltage-gated Ca(2+) channels, increase in cytoplasmic free Ca(2+) concentration, and enhanced glucagon release. In vivo blockade of iGluRs reduces glucagon secretion and exacerbates insulin-induced hypoglycemia in mice. Hence, the glutamate autocrine feedback loop endows the alpha cell with the ability to effectively potentiate its own secretory activity. This is a prerequisite to guarantee adequate glucagon release despite relatively modest changes in blood glucose concentration under physiological conditions.
葡萄糖稳态的一个重要特征是胰腺α细胞有效释放胰高血糖素。调节胰高血糖素分泌的分子机制仍知之甚少。我们现在证明，人类α细胞表达对胰高血糖素释放至关重要的离子型谷氨酸受体（iGluRs）。葡萄糖浓度降低会导致α细胞释放谷氨酸。然后谷氨酸作用于AMPA/海人藻酸型的iGluRs，导致膜去极化、电压门控Ca(2+)通道开放、细胞质游离Ca(2+)浓度增加以及胰高血糖素释放增强。体内阻断iGluRs会减少小鼠的胰高血糖素分泌并加重胰岛素诱导的低血糖。因此，谷氨酸自分泌反馈回路赋予α细胞有效增强其自身分泌活性的能力。这是在生理条件下尽管血糖浓度变化相对较小仍能保证足够胰高血糖素释放的先决条件。
