Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release

Cell Rep. 2019 Feb 5;26(6):1573-1584.e5. doi: 10.1016/j.celrep.2019.01.040.

Abstract

Insulin secretion from pancreatic β cells is a highly complex and tightly regulated process. Its dysregulation is one characteristic of type 2 diabetes, and thus, an in-depth understanding of the mechanisms controlling insulin secretion is essential for rational therapeutic intervention. G-protein-coupled receptors (GPCRs) have been established as major regulators of insulin exocytosis. Recent studies also suggest the involvement of adhesion GPCRs, a non-prototypical class of GPCRs. Here, we identify latrophilins, which belong to the class of adhesion GPCRs, to be highly expressed in different cell types of pancreatic islets. In vitro and ex vivo analyses show that distinct splice variants of the latrophilin LPHN3/ADGRL3 decrease insulin secretion from pancreatic β cells by reducing intracellular cyclic AMP levels via the Gi-mediated pathway. Our data highlight the key role of LPHN3 in modulating insulin secretion and its potential as therapeutic target for type 2 diabetes.

Keywords: adhesion GPCRs; insulin secretion; latrophilins; signaling; splice variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cyclic AMP / metabolism
  • HEK293 Cells
  • Humans
  • Insulin Secretion*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Peptide / genetics
  • Receptors, Peptide / metabolism*

Substances

  • LPHN3 protein, mouse
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Cyclic AMP