Functions of G protein‐coupled receptor 56 in health and disease

Abstract

Human G protein-coupled receptor 56 (GPR56) is encoded by gene ADGRG1 from chromosome 16q21 and is homologously encoded in mice, at chromosome 8. Both 687 and 693 splice forms are present in humans and mice. GPR56 has a 381 amino acid-long N-terminal extracellular segment and a GPCR proteolysis site upstream from the first transmembrane domain. GPR56 is mainly expressed in the heart, brain, thyroid, platelets, and peripheral blood mononuclear cells.Accumulating evidence indicates that GPR56 promotes the formation of myelin sheaths and the development of oligodendrocytes in the cerebral cortex of the central nervous system. Moreover, GPR56 contributes to the development and differentiation of hematopoietic stem cells, induces adipogenesis, and regulates the function of immune cells. The lack of GPR56 leads to nervous system dysfunction, platelet disorders, and infertility. Abnormal expression of GPR56 is related to the malignant transformation and tumor metastasis of several cancers including melanoma, neuroglioma, and gastrointestinal cancer. Metabolic disorders and cardiovascular diseases are also associated with dysregulation of GPR56 expression, and GPR56 is involved in the pharmacological resistance to some antidepressant and cancer drug treatments. In this review, the molecular structure, expression profile, and signal transduction of GPR56 are introduced, and physiological and pathological functions of GRP56 are comprehensively summarized.Attributing to its significant biological functions and its long N-terminal extracellular region that interacts with multiple ligands, GPR56 is becoming an attractive therapeutic target in treating neurological and hematopoietic diseases.

Ablation of GPR56 Causes β-Cell Dysfunction by ATP Loss through Mistargeting of Mitochondrial VDAC1 to the Plasma Membrane

“…The cumulating evidence makes GPR56 an interesting drug target in T2D. We and others have presented evidence that GPR56 is indeed capable of acting as a G-protein-coupling (Gαs type) to elicit downstream signaling cascades via the cAMP/PKA system in pancreatic β-cells [ 18 , 21 , 33 ], which was confirmed in the present work. A similar signal transduction has been shown for GpR56 activation by testosterone in prostate cells [ 24 ].…”

“…The rationale for the present investigations is the documented role of GPR56 in pancreatic β-cell survival and secretory function [ 18 , 19 , 21 , 25 , 33 ]. The expression level of GPR56 is positively correlated with the transcript level of a great number of genes with a beneficial impact on the β-cell fate in human pancreatic islets [ 18 ].…”

“…G-Protein-Coupled Receptors (GPCRs) constitute the largest group of cell surface receptors in men and are also the targets of ~35% of all prescription medicines [ 16 , 17 ]. G-Protein-Coupled Receptor 56 (GPR56), also known as Adhesion G-Protein-Coupled Receptor G1 (ADGRG1), is highly expressed in many tissues, including pancreatic β-cells [ 18 , 19 , 20 , 21 ]. Functionally, GPR56 has been linked to a myriad of biological and physiological processes within the cells, including the development and differentiation of cerebral cortex, innate immunity, muscle cell and oligodendrocyte development, and carcinogenesis, as well as affecting pancreatic β-cell function [ 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…G-Protein-Coupled Receptor 56 (GPR56), also known as Adhesion G-Protein-Coupled Receptor G1 (ADGRG1), is highly expressed in many tissues, including pancreatic β-cells [ 18 , 19 , 20 , 21 ]. Functionally, GPR56 has been linked to a myriad of biological and physiological processes within the cells, including the development and differentiation of cerebral cortex, innate immunity, muscle cell and oligodendrocyte development, and carcinogenesis, as well as affecting pancreatic β-cell function [ 18 , 19 , 20 , 21 , 22 , 23 ]. The GPR56 receptor is an adhesion receptor characterized by an extremely long N-terminal extracellular domain (NTD), which is cleaved off from the seven-membrane-spanning C-terminal domain (CTD) by auto-proteolysis upon binding to its principal ligand Collagen Type III.…”

“…Several studies have shown GPR56 coupling to the Gα12/13 class of heterotrimeric G-proteins to promote RhoA activation and alterations of the actin filamentous network [ 22 , 23 ]. GPR56 has also been reported to signal via Gαs to stimulate adenylate cyclase [ 18 , 24 ], as well as raising [Ca 2+ ] i through Gαq [ 19 ], although this was not clearly linked to Gαq since it is in contrast to ATP-induced [Ca 2+ ] i rise, which was abolished in the absence of extracellular Ca 2+ [ 19 ], suggesting the activation of calcium channels [ 20 , 21 ]. We have previously shown that GPR56 activation promotes β-cell viability and function both in human and rodents; in human pancreatic β-cells, GPR56 expression correlates with the expression levels of transcripts, vital for the function of β-cells and GPR56 mRNA, which is indeed reduced in islets of Type 2 diabetic organ donors [ 18 ].…”