Regulation of α‐cell function by Gs and Gq signaling

Authors

• L Liu
• K El
• L Barella
• Y Cui
• M Chen
• LS Weinstein
• JE Campbell
• J Wess

Abstract

Glucagon, an important islet hormone released from pancreatic α-cells, regulates systemic glucose homeostasis. Dysregulated glucagon secretion is a key feature of type 1 and 2 diabetes. However, the signaling pathways underlying the regulation of glucagon secretion remain incompletely understood. cAMP and Ca2+, the major intracellular second messengers downstream of Gs and Gq signaling, respectively, have been implicated in the regulation of glucagon secretion from of α-cells. In this study, we explored the relative physiological relevance of these signaling pathways by gene targeting technology in mice.

Specifically, we selectively deleted the α subunit of Gs or Gq in α-cells of adult mice (α-GsKO and α-Gq/11KO mice, respectively). Ablation of Gs or Gq signaling in α-cells caused reduced circulating glucagon, most likely due to decreased proglucagon gene expression and islet glucagon content. Disruption of α-cell Gs or Gq signaling also led to impaired glucagon secretion in response to hypoglycemic or glucopenic conditions, supporting the involvement of α-cell Gs- and Gq-coupled receptors in this effect. Perifusion studies showed that treatment of α-GsKO islets with ligands activating Gq-coupled receptors resulted in reduced glucagon secretion. Vice versa, α-Gq/11KO islets released reduced amounts of glucagon in response to ligands able to stimulate Gs-coupled receptors. Overall, these findings suggest that both α-cell Gs and Gq signaling are critical for glucagon secretion under various experimental conditions. Our data suggest that Gq activation engages pathways that require Gs signaling to effectively stimulate glucagon secretion and vice versa.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Monday, September 25, 2023