GPR162 is a beta cell CART receptor

Andreas Lindqvist; Mia Abels; Liliya Shcherbina; Mtakai Ngara; Dmytro Kryvokhyzha; Sabrina Chriett; Matteo Riva; Abul Fajul; Mohammad Barghouth; Cheng Luan; Lena Eliasson; Olav Larsen; Mette M Rosenkilde; Enming Zhang; Erik Renström; Nils Wierup

doi:10.1016/j.isci.2023.108416

GPR162 is a beta cell CART receptor

iScience. 2023 Nov 10;26(12):108416. doi: 10.1016/j.isci.2023.108416. eCollection 2023 Dec 15.

Authors

Affiliations

¹ Neuroendocrine Cell Biology, Lund University Diabetes Centre, Department for Experimental Medical Science, Lund University, CRC, Malmö, Sweden.
² Diabetic Complications, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, CRC, Malmö, Sweden.
³ Islet Pathophysiology, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, CRC, Malmö, Sweden.
⁴ Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, CRC, Malmö, Sweden.
⁵ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

Abstract

Cocaine and amphetamine-regulated transcript (CART) is expressed in pancreatic islet cells and neuronal elements. We have previously established insulinotropic actions of CART in human and rodent islets. The receptor for CART in the pancreatic beta cells is unidentified. We used RNA sequencing of Cartpt knockdown (KD) INS-1 832/13 cells and identified GPR162 as the most Cartpt-regulated receptor. We therefore tested if GPR162 mediates the effects of CART in beta cells. Binding of CART to GPR162 was established using proximity ligation assay, radioactive binding, and co-immunoprecipitation, and KD of Gpr162 mRNA caused reduced binding. Gpr162 KD cells had blunted CARTp-induced exocytosis, and reduced CARTp-induced insulin secretion. Furthermore, we identified a hitherto undescribed GPR162-dependent role of CART as a regulator of cytoskeletal arrangement. Thus, our findings provide mechanistic insight into the effect of CART on insulin secretion and show that GPR162 is the CART receptor in beta cells.

Keywords: Biological sciences; Endocrinology; Natural sciences; Physiology.