The adhesion receptor GPR56 is activated by extracellular matrix collagen III to improve β-cell function

Abstract

AimsG-protein coupled receptor 56 (GPR56) is the most abundant islet-expressed G-protein coupled receptor, suggesting a potential role in islet function. This study evaluated islet expression of GPR56 and its endogenous ligand collagen III, and their effects on β-cell function.MethodsGPR56 and collagen III expression in mouse and human pancreas sections was determined by fluorescence immunohistochemistry. Effects of collagen III on β-cell proliferation, apoptosis, intracellular calcium ([Ca2+]i) and insulin secretion were determined by cellular BrdU incorporation, caspase 3/7 activities, microfluorimetry and radioimmunoassay, respectively. The role of GPR56 in islet vascularisation and innervation was evaluated by immunohistochemical staining for CD31 and TUJ1, respectively, in pancreases from wildtype (WT) and Gpr56−/− mice, and the requirement of GPR56 for normal glucose homeostasis was determined by glucose tolerance tests in WT and Gpr56−/− mice.ResultsImmunostaining of mouse and human pancreases revealed that GPR56 was expressed by islet β-cells while collagen III was confined to the peri-islet basement membrane and islet capillaries. Collagen III protected β-cells from cytokine-induced apoptosis, triggered increases in [Ca2+]i and potentiated glucose-induced insulin secretion from WT islets but not from Gpr56−/− islets. Deletion of GPR56 did not affect glucose-induced insulin secretion in vitro and it did not impair glucose tolerance in adult mice. GPR56 was not required for normal islet vascularisation or innervation.ConclusionWe have demonstrated that collagen III improves islet function by increasing insulin secretion and protecting against apoptosis. Our data suggest that collagen III may be effective in optimising islet function to improve islet transplantation outcomes, and GPR56 may be a target for the treatment of type 2 diabetes.Electronic supplementary materialThe online version of this article (10.1007/s00018-018-2846-4) contains supplementary material, which is available to authorized users.

Adhesion G-protein coupled receptors: Implications for metabolic function

“…The functional significance of the ECM in normal islet function is well reported. Thus, ECM proteins are involved in a wide range of functions such as protecting -cells from apoptosis, enhancing insulin secretion, -cell migration and adhesion, and they play a role in pancreas development (Davis et al, 2012;Kaido et al, 2004;Huang et al, 2011;Shih et al, 2016;Arzouni et al, 2017;Llacua et al, 2018;Olaniru et al, 2018a).…”

“…insulin secretion and protects them from apoptosis, in a GPR56-dependent manner (Dunér et al, 2016;Olaniru, et al, 2018a), demonstrating that islets use -cell-expressed GPR56 to sense signals from ECM collagen III to improve -cell mass and secretory function. Consistent with this, islets in which GPR56 expression was acutely downregulated with siRNA had less insulin content and reduced insulin secretory capacity (Dunér et al, 2016).…”

Identifying novel therapeutic targets for diabetes through improved understanding of islet adhesion receptors

“…Another interesting member of the aGPCR family is GPR56. It is the most abundant islet GPCR [44], and it is expressed exclusively by the β-cells in islets [5]. Activation of islet GPR56 by its endogenous ligand, collagen III, has beneficial effects, including potentiation of glucose-stimulated insulin secretion and protection of islets against the deleterious effects of inflammation that occur in diabetes [5,47].…”

“…It is the most abundant islet GPCR [44], and it is expressed exclusively by the β-cells in islets [5]. Activation of islet GPR56 by its endogenous ligand, collagen III, has beneficial effects, including potentiation of glucose-stimulated insulin secretion and protection of islets against the deleterious effects of inflammation that occur in diabetes [5,47]. Moreover, a recent study has shown that pre-treating human islets with mesenchymal stromal cell-derived ECM, which is rich in the GPR56 agonist collagen III, led to enhanced insulin output [2].…”

“…Earlier observations in which isolated β-cells secreted less insulin than -cells within intact islets point to the importance of intercellular contacts and cellular organisation in islet function [1]. Moreover, there are several reports that islets exposed to extracellular matrix (ECM) proteins exhibit increased survival and improved insulin secretion [2][3][4][5], which is suggestive of an important role for islet-matrix interactions in appropriate regulation of glucose homeostasis.…”