Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release
Juliane Röthe,
Doreen Thor,
Jana Winkler,
Alexander B. Knierim,
Claudia Binder,
Sandra Huth,
Robert Kraft,
Sven Rothemund,
Torsten Schöneberg,
Simone Prömel
Affiliations
Juliane Röthe
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany; Leipzig University Medical Center, IFB AdiposityDiseases, 04103 Leipzig, Germany
Doreen Thor
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany; Corresponding author
Jana Winkler
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany
Alexander B. Knierim
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany; Leipzig University Medical Center, IFB AdiposityDiseases, 04103 Leipzig, Germany
Claudia Binder
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany
Sandra Huth
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany
Robert Kraft
Carl Ludwig Institute for Physiology, Medical Faculty, Leipzig University, 04103 Leipzig, Germany
Sven Rothemund
Core Unit Peptide Technologies, Medical Faculty, Leipzig University, 04103 Leipzig, Germany
Torsten Schöneberg
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany
Simone Prömel
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103 Leipzig, Germany; Corresponding author
Summary: 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. : With diabetes becoming an epidemic disease, understanding processes regulating insulin secretion is a major task. Röthe et al. show that tissue-specific splice variants of the adhesion GPCR Latrophilin-3 in pancreatic islets modulate insulin secretion. In contrast to other variants, they reduce intracellular cAMP via a Gi protein pathway. Keywords: adhesion GPCRs, latrophilins, insulin secretion, signaling, splice variants
