Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells

Liu, Jinpeng; Komachi, Mayumi; Tomura, Hideaki; Mogi, Chihiro; Damirin, Alatangaole; Tobo, Masayuki; Takano, Mutsumi; Nochi, Hiromi; Tamoto, Koichi; Sato, Kōichi; Okajima, Fumikazu

doi:10.1152/ajpheart.00977.2009

Cited by 27 publications

(24 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…44,47 increases expression of cardiomyogenic and pro-survival genes in the heart; as well as mediates gene expression in aortic smooth muscle cells. [50][51][52] Renal N/A Regulates renal acid excretion in mice and H + -K + -ATPase expression. 59,60 Regulates proton transporter activity and proton extrusion in the kidney.…”

Section: Acknowledgmentsmentioning

confidence: 99%

“…51 Additionally, acidic pH-induced vascular actions of aortic smooth muscle cells can be divided into GPR68-dependent effects such as COX-2 expression, PGI 2 production, and MAPK phosphatase-1 expression and GPR68-independent effects such as PAI-1 expression and cell proliferation. 52 Taken together, both GPR4 and GPR68 play roles in regulating the function of the cardiovascular system. GPR4 regulates blood vessel stability and endothelial cell function and GPR68 increases cardiomyogenic and pro-survival gene expression while also mediating aortic smooth muscle cell gene expression.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

View full text Add to dashboard Cite

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.

show abstract

Section: Acknowledgmentsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

View full text Add to dashboard Cite

show abstract

“…OGR1 has now been reported to be involved in a variety of physiologically important responses to extracellular acidification using a knockdown strategy of the receptor in several types of cells in vitro, i.e. RANKL-induced differentiation in osteoclasts (5), Ca 2ϩ mobilization, cyclooxygenase-2 induction, and prostaglandin synthesis in osteoblasts (6,7) and vascular smooth muscle cells (8,9), and IL-6 production in airway smooth muscle cells (10). Moreover, a study using OGR1 knockout mice suggested that OGR1 is involved in tumorigenesis in vivo (11).…”

mentioning

confidence: 99%

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

Nakakura¹,

Mogi²,

Tobo³

et al. 2012

Endocrinology

Self Cite

View full text Add to dashboard Cite

Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of G q/11 proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca 2ϩ concentration. In conclusion, the OGR1/G q/11 protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl. (Endocrinology 153: 4171-4180, 2012)

show abstract

“…In fact, OGR1 has been reported to be involved in a variety of physiologically important responses to extracellular acidification using a knockdown strategy of the receptor in several types of cells in vitro, e.g., receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation in osteoclasts [42], Ca 2+ mobilization, cyclooxygenase (COX)-2 induction, and prostaglandin synthesis in osteoblasts [43,44] and vascular smooth muscle cells [45,46], and IL-6 and connective tissue growth factor production in airway smooth muscle cells [47][48][49]. Similarly, TDAG8 has been shown to mediate acidic pH-induced inhibition of apoptosis in eosinophils [50], inflammatory cytokine production in macrophages [51], and O 2 -production in neutrophils [52].…”

Section: In Vitro Analysis Of Insulin Secretionmentioning

confidence: 99%

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

2014

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells

Cited by 27 publications

References 62 publications

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

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

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

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

Contact Info

Product

Resources

About