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.

/pdf/adipose-tissue-secretion-pattern-influences-b-cell-wellness-1mk1rhrf.pdf

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

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 KD of 1.56 × 10-10  M. In GPR75-transfected HTLA cells, 20-HETE stimulated intracellular Ca2+ 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 Ca2+ . The chemokine CCL5, a suggested GPR75 ligand, binds to GPR75 (KD of 5.85 × 10-10  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.

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

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.

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

Eicosanoid signaling controls a wide range of biological processes from blood pressure homeostasis to inflammation and resolution thereof to the perception of pain and to cell survival itself. Disruption of normal eicosanoid signaling is implicated in numerous disease states. Eicosanoid signaling is facilitated by G-protein-coupled, eicosanoid-specific receptors and the array of associated G-proteins. This review focuses on the expression, characterization, regulation, and mechanism of action of non-prostanoid, eicosanoid receptors.

A review of non-prostanoid, eicosanoid receptors: expression, characterization, regulation, and mechanism of action

G protein-coupled receptors (GPCRs) orchestrate many physiological functions and are a crucial target in drug discovery. Adhesion GPCRs (aGPCRs), the second largest family within this superfamily, are promising yet underexplored targets for treating various diseases, including obesity, psychiatric disorders, and cancer. However, the receptors' unique and complex structure and miscellaneous interactions complicate comprehensive pharmacological studies. Despite recent progress in determining structures and elucidation of the activation mechanism, the function of many receptors remains to be determined. This review consolidates current knowledge on aGPCR ligands, focusing on small molecule orthosteric ligands and allosteric modulators identified for the ADGRGs subfamily (subfamily VIII), (GPR56/ADGRG1, GPR64/ADGRG2, GPR97/ADGRG3, GPR114/ADGRG5, GPR126/ADGRG6, and GPR128/ADGRG7). We discuss challenges in hit identification, target validation, and drug discovery, highlighting molecular compositions and recent structural breakthroughs. ADGRG ligands can offer new insights into aGPCR modulation and have significant potential for novel therapeutic interventions targeting various diseases. 

Targeting adhesion G protein-coupled receptors. Current status and future perspectives

Background/aim The polypeptide hormone insulin is essential for the maintenance of whole-body fuel homeostasis, and defects in insulin secretion and/or action are associated with the development of type 1 and type 2 diabetes. The aim of this study was to assess the role of some G-protein coupled receptors (GPCRs), GPR54, GPR56, and GPR75, and cannabinoid receptors CB1R and CB2R, in the regulation of pancreatic β-cell function. Materials and methods Insulin secretion from mouse insulinoma β-cell line (MIN6) monolayers was assessed via insulin radioimmu-noassay (RIA). Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the expression of some specific GPCRs and the other receptors by MIN6 pancreatic β-cells. Results The agonists were not found to be toxic for the MIN6 pancreatic β-cells within the range of the doses used in this study, whereas insulin secretion altered depending on the ligands and receptors. In addition, arachidonyl-2’-chloroethylamide (ACEA), carbachol, chemokine (C-C motif ) ligand-5 (CCL5), and exendin as well as phorbol myristate acetate (PMA) ligands showed significant increases in the insulin secretion of MIN6 pancreatic β-cells. Conclusion Understanding the normal β-cell function and identifying the defects in β-cell function that lead to the development of diabetes will generate new therapeutic targets

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

Gap junctions (GJ) are the most important cell-to-cell structures; that plays the role of intercellular communication and maintenance of cellular homeostasis in epithelium, muscle and neural tissues and also in more tissues and organs. These communication domains and also their composer proteins are called "connexins" and they show a wide range in all of the mammalian cells. Six connexin monomers join together and form a hemichannel called "connexon". The different types of connexons bind the cell to an adjacent connexon and make the cell ready for gap junctional intercellular communication (GJIC). In last years, recent data of concerned experiements show that the structural precursors of gap junctions; connexins and in attendance connexons or hemichannels, can affect the cellular homeostatic balance independently of gap junctional intercellular communication (GJIC). In this review, the role of connexins and their channels with connexin diversity mentioned and also the cell cycle of them are discussed.

The role of connexins in intercellular communication (a review)

/pdf/deneysel-otizm-spektrum-bozuklugu-modeli-olusturulan-puqqq0wbmw.pdf

Deneysel Otizm Spektrum Bozukluğu Modeli Oluşturulan Sıçanlarda Likopenin Beyin IL–6, IL–10, FGF–2 ve NGF Düzeyleri Üzerine Etkisi

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

The role of connexins in intercellular communication (a review)

Deneysel Otizm Spektrum Bozukluğu Modeli Oluşturulan Sıçanlarda Likopenin Beyin IL–6, IL–10, FGF–2 ve NGF Düzeyleri Üzerine Etkisi