Determining the insulin secretion potential for certain specific G-protein coupled receptors in MIN6 pancreatic beta cells

Gençoğlu, Hasan; Şahin, Kazım; Jones, Peter M.

doi:10.3906/sag-1712-147

Cited by 4 publications

(5 citation statements)

References 22 publications

(22 reference statements)

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“…Accordingly, RANTES/CCL5, through the activation of the CCRs, reduces glucose-stimulated GLP-1 secretion in the human enteroendocrine cell line NCI-H716 and in mice in vivo, resulting in impaired insulin secretion after glucose stimulation in mice [ 238 ]. On the other hand, via GPR75, RANTES/CCL5 stimulates insulin secretion from β-cell lines [ 239 ] and mouse and human pancreatic islets in vitro, and improves glucose tolerance in lean mice and a mouse model of hyperglycaemia and insulin resistance without changing insulin sensitivity [ 237 ]. Interestingly, it has been demonstrated that adiponectin can negatively regulate the expression of RANTES/CCL5 [ 240 ].…”

Section: Dysfunctional Adipose Tissue Secretome Affects β-Cell Functi...mentioning

confidence: 99%

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

Biondi

Marrano

Borrelli

et al. 2022

IJMS

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The dysregulation of the β-cell functional mass, which is a reduction in the number of β-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a leading cause of β-cell loss and dysfunction and a risk factor for T2D. The natural history of β-cell failure in obesity-induced T2D can be divided into three steps: (1) β-cell compensatory hyperplasia and insulin hypersecretion, (2) insulin secretory dysfunction, and (3) loss of β-cell mass. Adipose tissue (AT) secretes many hormones/cytokines (adipokines) and fatty acids that can directly influence β-cell function and viability. As this secretory pattern is altered in obese and diabetic patients, it is expected that the cross-talk between AT and pancreatic β-cells could drive the maintenance of the β-cell integrity under physiological conditions and contribute to the reduction in the β-cell functional mass in a dysmetabolic state. In the current review, we summarise the evidence of the ability of the AT secretome to influence each step of β-cell failure, and attempt to draw a timeline of the alterations in the adipokine secretion pattern in the transition from obesity to T2D that reflects the progressive deterioration of the β-cell functional mass.

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Section: Dysfunctional Adipose Tissue Secretome Affects β-Cell Functi...mentioning

confidence: 99%

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

Biondi

Marrano

Borrelli

et al. 2022

IJMS

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“…GPR56 is the most abundantly expressed aGPCR in β cells of human and murine islets, indicating an important role in islet function. Moreover, insulin‐secreting MIN6 mouse insulinoma cells express high levels of GPR56 mRNA 66 . GPR56 mRNA expression in human islets is negatively correlated to β‐cell function and type 2 diabetes (T2D) risks.…”

Section: Physiological Role Of Gpr56mentioning

confidence: 99%

“…Moreover, insulin-secreting MIN6 mouse insulinoma cells express high levels of GPR56 mRNA. 66 GPR56 mRNA expression in human islets is negatively correlated to βcell function and type 2 diabetes (T2D) risks. Reduced GPR56 expression has been found in islets from T2D patients, db/db mice, and normal human islets chronically treated ex vivo in hyperglycaemic conditions.…”

Section: Physiological Role Of Gpr56 In Metabolismmentioning

confidence: 99%

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

Guan

Cheng

et al. 2022

Acta Physiologica

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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.

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“…No direct binding studies of CCL5 to GPR75 were documented in that study. Recent studies reported that pancreatic islets as well as beta cell lines express GPR75 and that CCL5 stimulates insulin secretion via PLC‐activated Ca 2+ influx in a GPR75‐dependent manner; however, they also did not document direct binding or interaction between GPR75 and CCL5 (Gencoglu et al, 2019; Liu et al, 2013). Importantly, the pairing of CCL5 and GPR75 could not be repeated in a β‐arrestin assay (Davenport et al, 2013; Dedoni et al, 2018; Southern et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Uncovering the signalling, structure and function of the 20‐HETE‐GPR75 pairing: Identifying the chemokine CCL5 as a negative regulator of GPR75

Pascale

Park

Adebesin

et al. 2021

British J Pharmacology

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Background and Purpose: The G-protein-coupled receptor GPR75 (Gq) and its ligand, the cytochrome P450-derived vasoactive eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE), are involved in the activation of pro-inflammatory and hypertensive signalling cascades contributing to diabetes, obesity, vascular dysfunction/remodelling, hypertension and cardiovascular disease. Little is known as to how, where and with what affinity 20-HETE interacts with GPR75. Experimental Approach: To better understand the pairing of 20-HETE and its receptor (GPR75), we used surface plasmon resonance (SPR) to determine binding affinity/kinetics. The PRESTO-Tango receptor-ome methodology for GPR75 overexpression was coupled with FLIPR Calcium 6 assays, homogeneous time-resolved fluorescence (HTRF) IP-1 and β-arrestin recruitment assays to determine receptor activation and downstream signalling events. Key Results: SPR confirmed 20-HETE binding to GPR75 with an estimated K D of 1.56 Â 10 À10 M. In GPR75-transfected HTLA cells, 20-HETE stimulated intracellular Ca 2+ levels, IP-1 accumulation and β-arrestin recruitment, all of which were negated by known 20-HETE functional antagonists. Computational modelling of the putative ligand-binding pocket and mutation of Thr212 within the putative 20-HETE binding site abolished 20-HETE's ability to stimulate GPR75 activation. Knockdown of GPR75 in human endothelial cells nullified 20-HETE-stimulated intracellular Ca 2+ .The chemokine CCL5, a suggested GPR75 ligand, binds to GPR75 (K D of 5.85 Â 10 À10 M) yet fails to activate GPR75; however, it inhibited 20-HETE's ability to activate GPR75 signalling. Conclusions and Implications:We have identified 20-HETE as a high-affinity ligand for GPR75 and CCL5 as a low-affinity negative regulator of GPR75, providing additional evidence for the deorphanization of GPR75 as a 20-HETE receptor.

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Determining the insulin secretion potential for certain specific G-protein coupled receptors in MIN6 pancreatic beta cells

Cited by 4 publications

References 22 publications

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

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

Uncovering the signalling, structure and function of the 20‐HETE‐GPR75 pairing: Identifying the chemokine CCL5 as a negative regulator of GPR75

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