Glutamate Is a Positive Autocrine Signal for Glucagon Release

Over Cabrera, M. Caroline Jacques-Silva, Stephan Speier, Shao Nian Yang, Martin Köhler, Alberto Fachado, Elaine Vieira, Juleen R. Zierath, Richard Kibbey, Dora M. Berman, Norma S. Kenyon, Camillo Ricordi, Alejandro Caicedo, Per Olof Berggren

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


An important feature of glucose homeostasis is the effective release of glucagon from the pancreatic α cell. The molecular mechanisms regulating glucagon secretion are still poorly understood. We now demonstrate that human α 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 α cell. Glutamate then acts on iGluRs of the AMPA/kainate type, resulting in membrane depolarization, opening of voltage-gated Ca2+ channels, increase in cytoplasmic free Ca2+ 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 α 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.

Original languageEnglish (US)
Pages (from-to)545-554
Number of pages10
JournalCell Metabolism
Issue number6
StatePublished - Jun 4 2008



ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology


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