Adhesion G Protein-Coupled Receptor G1 (ADGRG1/GPR56) and Pancreatic β-Cell Function

Dunér, Pontus; Al-Amily, Israa Mohammad; Soni, Arvind; Asplund, Olof; Safi, Fateme; Storm, Petter; Groop, Leif; Amisten, Stefan; Salehi, Albert

doi:10.1210/jc.2016-1884

Cited by 57 publications

(78 citation statements)

References 39 publications

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“…Since Gpr142 was abundantly expressed in β-cells with a marked impact on the GSIS, we performed Gpr142 -KD in INS-1832/13 cells and compared the expression level of Gpr142 to several other Gpcrs , i.e., Gpcrs with G q/o (Ffar1, Ffar2, and Ffar3) or Gpcrs with G s -coupling (Gpr56) reportedly impacting at least in part, different down-stream signaling pathway [9, 27]. As the release of cytokines was increased upon Gpr143 -KD, we also measured the expression of Tlr5 and Tlr7 two receptors involved in mediating inflammatory signals in pancreatic β-cells [33].…”

Section: Resultsmentioning

confidence: 99%

“…Gpr142 was downregulated in mouse islets using a cocktail of different Lenti-virus delivered shRNAs targeting the Gpr142 gene (sc-145707) (Santa Cruz, CA, USA) as we have described elsewhere for knockdown of other GPCRs [9, 39]. For downregulation of Gpr142 in rat INS-1832/13 cells, siRNAs (s180594) from Applied Biosystems (USA), with an appropriate scrambled control (4390846), were used according to the manufacturer’s recommendations.…”

Section: Methodsmentioning

confidence: 99%

“…After transfection (36 h) and a recovery period (6 h), the medium was changed and the cells were cultured for additional 72 h in normal RPMI 1640 culture medium at 37 °C with 5% ambient CO 2 . The cells (in individual wells) were then harvested by trypsination and counted using a Bürcker chamber [9]. …”

Section: Methodsmentioning

confidence: 99%

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The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

Al-Amily

Dunér

Groop

et al. 2019

Pflugers Arch - Eur J Physiol

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We have recently shown that the G protein-coupled receptor 142 (GPR142) is expressed in both rodent and human pancreatic β-cells. Herein, we investigated the cellular distribution of GPR142 within islets and the effects of selective agonists of GPR142 on glucose-stimulated insulin secretion (GSIS) in the mouse islets and INS-1832/13 cells. Double-immunostaining revealed that GPR142 immunoreactivity in islets mainly occurs in insulin-positive cells. Potentiation of GSIS by GPR142 activation was accompanied by increased cAMP content in INS-1832/13 cells. PKA/Epac inhibition markedly suppressed the effect of GPR142 activation on insulin release. Gpr142 knockdown (Gpr142-KD) in islets was accompanied by elevated release of MCP-1, IFNγ, and TNFα during culture period and abolished the modulatory effect of GPR142 activation on the GSIS. Gpr142-KD had no effect on Ffar1, Ffar2, or Ffar3 mRNA while reducing Gpr56 and increasing Tlr5 and Tlr7 mRNA expression. Gpr142-KD was associated with an increased expression of Chrebp, Txnip, RhoA, and mitochondrial Vdac1 concomitant with a reduced Pdx1, Pax6, and mitochondrial Vdac2 mRNA levels. Long-term exposure of INS-1832/13 cells to hyperglycemia reduced Gpr142 and Vdac2 while increased Chrebp, Txnip, and Vdac1 mRNA expression. GPR142 agonists or Bt2-cAMP counteracted this effect. Glucotoxicity-induced decrease of cell viability in Gpr142-KD INS-1 cells was not affected by GPR142-agonists while Bt2-cAMP prevented it. The results show the importance of Gpr142 in the maintenance of pancreatic β-cell function in rodents and that GPR142 agonists potentiate GSIS by an action, which most likely is due to increased cellular generation of second messenger molecule cAMP.Electronic supplementary materialThe online version of this article (10.1007/s00424-019-02262-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

Al-Amily

Dunér

Groop

et al. 2019

Pflugers Arch - Eur J Physiol

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“…Examples of locally produced peptide ligands of islet GPCRs include glucagon and somatostatin, which act in a paracrine function to regulate secretion of islet hormones from neighbouring cells [2]. In addition, collagen III and IV, which are components of the extracellular matrix that supports islet cells, interact with the islet-expressed GPCRs, GPR56 and GPR126 [3–5]. GPCR peptide ligands that are delivered to islets in the circulation include the incretin hormones GLP-1 and GIP, which are secreted by specialised enteroendocrine cells in the gastrointestinal tract [6], and it has recently been reported that the cardiomyocyte-derived atrial natriuretic peptide stimulates insulin secretion via activation of β-cell guanylate cyclase-coupled GC-A receptors [7].…”

Section: Introductionmentioning

confidence: 99%

Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

Atanes

Ruz‐Maldonado

Hawkes

et al. 2018

Cell. Mol. Life Sci.

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IntroductionIslets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets.Materials and methodsGPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches in the PubMed, IUPHAR and Ingenuity databases. Distribution of PYY protein in mouse and human islets was determined by immunohistochemistry. Insulin, glucagon and somatostatin secretion from islets was measured by radioimmunoassay.ResultsWe have quantified GPCR peptide ligand mRNA expression in human and mouse islets and created specific signalomes mapping the pathways by which islet peptide ligands regulate human and mouse GPCR signalling. We also identified species-specific islet expression of several GPCR ligands. In particular, PYY mRNA levels were ~ 40,000-fold higher in mouse than human islets, suggesting a more important role of locally secreted Pyy in mouse islets. This was confirmed by IHC and functional experiments measuring insulin, glucagon and somatostatin secretion.DiscussionThe detailed human and mouse islet GPCR peptide ligand atlases will allow accurate translation of mouse islet functional studies for the identification of GPCR/peptide signalling pathways relevant for human physiology, which may lead to novel treatment modalities of diabetes and metabolic disease.Electronic supplementary materialThe online version of this article (10.1007/s00018-018-2778-z) contains supplementary material, which is available to authorized users.

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“…GPR56 does not appear to be required for survival of adult mammals since knockout mice are viable [25]. Although GPR56 may also interact with tissue collagen III and transglutaminase 2 [26, 27], specific ligands have not been identified and GPR56 has remained classified as an “orphan receptor” with unknown functions.…”

Section: Introductionmentioning

confidence: 99%

The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis

et al. 2017

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Overexpression of human progastrin increases colonic mucosal proliferation and colorectal cancer progression in mice. The G-protein coupled receptor 56 (GPR56) is known to regulate cell adhesion, migration, proliferation and stem cell biology, but its expression in the gut has not been studied. We hypothesized that the promotion of colorectal cancer by progastrin may be mediated in part through GPR56. Here, we found that GPR56 expresses in rare colonic crypt cells that lineage trace colonic glands consistent with GPR56 marking long-lived colonic stem-progenitor cells. GPR56 was upregulated in transgenic mice overexpressing human progastrin. While recombinant human progastrin promoted the growth and survival of wild-type colonic organoids in vitro, colonic organoids cultured from GPR56−/− mice were resistant to progastrin. We found that progastrin directly bound to, and increased the proliferation of, GPR56-expressing colon cancer cells in vitro, and proliferation was increased in cells that expressed both GPR56 and the cholecystokinin-2 receptor (CCK2R). In vivo, deletion of GPR56 in the mouse germline abrogated progastrin-dependent colonic mucosal proliferation and increased apoptosis. Loss of GPR56 also inhibited progastrin-dependent colonic crypt fission and colorectal carcinogenesis in the azoxymethane (AOM) mouse model of colorectal cancer. Overall, we found that progastrin binds to GPR56 expressing colonic stem cells, which in turn promotes their expansion, and that this GPR56-dependent pathway is an important driver and potential new target in colorectal carcinogenesis.

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Adhesion G Protein-Coupled Receptor G1 (ADGRG1/GPR56) and Pancreatic β-Cell Function

Abstract: We demonstrate a mechanistic link between ADGRG1 expression and β-cell function. Pharmacological agents that promote expression or activation of the ADGRG1 receptor may represent a novel approach for the treatment of T2D.

Cited by 57 publications

References 39 publications

The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic β-cell in rodent

Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis

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