Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Nakakura, Takashi; Mogi, Chihiro; Tobo, Masayuki; Tomura, Hideaki; Sato, Kōichi; Kobayashi, Masaki; Ohnishi, Hiroshi; Tanaka, Shigeyasu; Wayama, Mitsutoshi; Sugiyama, Tetsuya; Kitamura, Tadahiro; Harada, Akira; Okajima, Fumikazu

doi:10.1210/en.2012-1164

Cited by 35 publications

(43 citation statements)

References 33 publications

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“…If they did not adjust pH of the KRH buffer containing lactisole, pH of the buffer may have been lower than should be. Because b-cells express the proton receptor (Nakakura et al 2012), low pH might have stimulated insulin secretion independent of the action of lactisole. Further studies are necessary to address these points.…”

Section: Cmentioning

confidence: 99%

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Hamano¹,

Nakagawa²,

Ohtsu³

et al. 2015

Journal of Endocrinology

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Glucose activates the glucose-sensing receptor T1R3 and facilitates its own metabolism in pancreatic b-cells. An inhibitor of this receptor would be helpful in elucidating the physiological function of the glucose-sensing receptor. The present study was conducted to examine whether or not lactisole can be used as an inhibitor of the glucose-sensing receptor. In MIN6 cells, in a dose-dependent manner, lactisole inhibited insulin secretion induced by sweeteners, acesulfame-K, sucralose and glycyrrhizin.

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Section: Cmentioning

confidence: 99%

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Hamano¹,

Nakagawa²,

Ohtsu³

et al. 2015

Journal of Endocrinology

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“…Recently, the pH-sensing GPCRs, GPR4 and GPR68, have been found to be involved in insulin secretion and tissue sensitivity to insulin. 83,84 In GPR4 knockout mice glucose tolerance was augmented by increasing the sensitivity to insulin. 83 The balance of proinflammatory and anti-inflammatory molecules are crucial for the maintenance of insulin sensitivity as pro-inflammatory cytokines can further promote insulin resistance and type II diabetes.…”

Section: Role For the Ph-sensing Gpcrs In The Endocrine Systemmentioning

confidence: 99%

“…In GPR68 knockout mice insulin secretion in response to glucose administration was reduced when compared to wild-type mice although blood glucose was not significantly altered. 84 GPR68 deficiency in this respect may reduce insulin secretion but at the same time increase insulin sensitivity. In addition, stimulation of GPR68 in islet cells by acidosis increased the secretion of insulin through the G q/11 G-protein signaling.…”

Section: Role For the Ph-sensing Gpcrs In The Endocrine Systemmentioning

confidence: 99%

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

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Protons (hydrogen ions) are the simplest form of ions universally produced by cellular metabolism including aerobic respiration and glycolysis. Export of protons out of cells by a number of acid transporters is essential to maintain a stable intracellular pH that is critical for normal cell function. Acid products in the tissue interstitium are removed by blood perfusion and excreted from the body through the respiratory and renal systems. However, the pH homeostasis in tissues is frequently disrupted in many pathophysiologic conditions such as in ischemic tissues and tumors where protons are overproduced and blood perfusion is compromised. Consequently, accumulation of protons causes acidosis in the affected tissue. Although acidosis has profound effects on cell function and disease progression, little is known about the molecular mechanisms by which cells sense and respond to acidotic stress. Recently a family of pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), has been identified and characterized. These GPCRs can be activated by extracellular acidic pH through the protonation of histidine residues of the receptors. Upon activation by acidosis the pH-sensing GPCRs can transduce several downstream G protein pathways such as the G s , G q/11 , and G 12/13 pathways to regulate cell behavior. Studies have revealed the biological roles of the pH-sensing GPCRs in the immune, cardiovascular, respiratory, renal, skeletal, endocrine, and nervous systems, as well as the involvement of these receptors in a variety of pathological conditions such as cancer, inflammation, pain, and cardiovascular disease. As GPCRs are important drug targets, small molecule modulators of the pH-sensing GPCRs are being developed and evaluated for potential therapeutic applications in disease treatment.

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“…Among the tissues and organs involved in glucose metabolism, OGR1 is expressed in adipose tissues but not in liver and skeletal muscle [61]. This reminds us the similarity of the phenotypes of knockout mice of ASIC3, which improve glucose tolerance and insulin sensitivity probably through the change in adipocyte functions [34].…”

Section: General Information Regarding Proton-sensing Gpcrsmentioning

confidence: 82%

“…With respect to glucose utilization, the inhibitory role of proton/OGR1 in glucose utilization might be related to the finding of Yajima and Ui that alkalosis is stimulatory, whereas acidosis is inhibitory, for glucose utilization [2,3]. According to Nakakura et al [61], OGR1 seems to be inhibitory for glucose utilization at normal or physiological pH values. If so, alkalosis may reduce OGR1 activity by decreasing proton or ligand concentrations and thereby de-inhibit or stimulate glucose utilization activity or insulin sensitivity.…”

Section: General Information Regarding Proton-sensing Gpcrsmentioning

confidence: 92%

Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions

2014

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Abstract. Insulin secretion with respect to pH environments has been investigated for a long time but its mechanism remains largely unknown. Extracellular pH is usually maintained at around 7.4 and, its change has been thought to occur in non-physiological situations. Acidification takes place under ischemic and inflammatory microenvironments, where stimulation of anaerobic glycolysis results in the production of lactic acid. In addition to ionotropic ion channels, such as transient receptor potential V1 (TRPV1) and acid-sensing ion channels (ASICs), metabotropic proton-sensing G proteincoupled receptors (GPCRs) have also been identified recently as proton-sensing machineries. While ionotropic ion channels usually sense strong acidic pH, proton-sensing GPCRs sense pH of 7.6 to 6.0 and have been shown to mediate a variety of biological actions in neutral and mildly acidic pH environments. Studies with receptor knockout mice have revealed that proton-sensing receptors, including ovarian cancer G protein-coupled receptor 1 (OGR1), a proton-sensing GPCRs, play a role in the regulation of insulin secretion and glucose metabolism under physiological conditions. Small molecule 3,5-disubstituted isoxazoles have recently been identified as OGR1 agonists working at neutral pH and have been shown to stimulate pancreatic β-cell differentiation and insulin synthesis. Thus, proton-sensing OGR1 may be an important player for insulin secretion and a potential target for improving β-cell function.

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Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Cited by 35 publications

References 33 publications

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions

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