Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

Latif Rachdi,Severine Pechberty,Olivier Albagli,Juliette Hamroune,Raphael Scharfmann,Alicia Maugein,Philippe Ravassard,Mathieu Armanet,Stefano Marullo

doi:10.1038/s41598-020-69758-6

Abstract

G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. They constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases. We generated a new stable human beta cell line from neonatal pancreas. This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABAB receptor compared to human islet. In ECN90 cells, baclofen, a specific GABAB receptor agonist, inhibits cAMP signaling causing decreased expression of beta cell-specific genes such as MAFA and PCSK1, and reduced insulin secretion. We next demonstrated that in primary human islets, GABBR2 mRNA expression is strongly induced under cAMP signaling, while GABBR1 mRNA is constitutively expressed. We also found that induction and activation of the GABAB receptor in human islets modulates insulin secretion.

Highlights

G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes
The GABAA receptor is a five-subunits chloride ion channel whereas the GABAB receptor is a G protein-coupled receptors (GPCRs) heterodimer composed of two subunits, GABBR1 and GABBR2
A specific synthetic agonist of the G ABAB receptor[14], we demonstrated that the G ABAB receptor is functional and modulates beta cell differentiation and insulin secretion in ECN90 cells

Summary

Introduction

G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. We generated a new stable human beta cell line from neonatal pancreas This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABAB receptor compared to human islet. In ECN90 cells, baclofen, a specific GABAB receptor agonist, inhibits cAMP signaling causing decreased expression of beta cellspecific genes such as MAFA and PCSK1, and reduced insulin secretion. G protein-coupled receptors (GPCRs), which modulate a variety of physiological responses, are potential targets for anti-diabetic c ompounds[2] These seven transmembrane receptors are coupled to heterotrimeric G proteins, such as Gαs, Gαi/o, Gαq/11 and Gα12/13. We investigated G ABAB receptor signaling in human beta cells using in a newly developed human beta cell line, ECN90 cells Both GABBR1 and GABBR2 subunits are expressed in these cells.

Methods

Results

Conclusion