Activation of GPR4 by Acidosis Increases Endothelial Cell Adhesion through the cAMP/Epac Pathway

Chen, Aishe; Dong, Lixue; Leffler, Nancy R.; Asch, Adam S.; Witte, Owen N.; Yang, Li V.

doi:10.1371/journal.pone.0027586

Cited by 116 publications

(193 citation statements)

References 77 publications

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“…32 Moreover, human umbilical vein endothelial cells, when treated with acidic pH, increased GPR4-mediated endothelial adhesion to leukocytes. 32,33 Altogether, GPR65 and GPR4 provide differential regulation of the inflammatory response through their acid sensing capabilities. GPR65 predominately demonstrates function in the inhibition of the inflammatory response whereas GPR4 activation exacerbates inflammation.…”

Section: Gpr65 (Tdag8)mentioning

confidence: 99%

“…The GPR4 receptor is highly expressed in vascular endothelial cells. 33,44 GPR4 is activated by extracellular acidic pH to initiate signaling cascades which regulate cellular function. 19,33,45,46 It has been reported that GPR4 is a functional pH sensor in vascular …”

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

confidence: 99%

“…83 GPR4 is also highly expressed in endothelial cells, which when activated has been reported to stimulate the expression of inflammatory genes. 32,33 GPR68 has also been found to modify insulin production and secretion. 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.…”

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

confidence: 99%

“…GPR4, GPR65, and GPR68 play roles in tumor cell apoptosis, proliferation, metastasis, angiogenesis, and immune cell function. 19,27,32,33,44,45,96,97 GPR4 has had conflicting reports in terms of tumor suppressing or promoting activities. One study demonstrated that GPR4 could act as a tumor metastasis suppressor, when overexpressed and activated by acidic pH in B16F10 melanoma cells, by impeding migration and invasion of tumor cells.…”

mentioning

confidence: 99%

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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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Section: Gpr65 (Tdag8)mentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

mentioning

confidence: 99%

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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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“…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]. As for GPR4, this receptor subtype has been reported to mediate acidic-pH-induced stimulation of monocyte adhesion in association with the expression of VCAM-1 [53] and a number of inflammatory genes [54]. In these previous studies, protonsensing GPCRs mediate responses to acidic environments of less than pH 7.0, which may be attained under inflammatory lesions [39].…”

Section: In Vitro Analysis Of Insulin Secretionmentioning

confidence: 98%

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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Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression

Boedtkjer

2021

Reviews of Physiology, Biochemistry and Pharmacology

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Activation of GPR4 by Acidosis Increases Endothelial Cell Adhesion through the cAMP/Epac Pathway

Cited by 116 publications

References 77 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

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

Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression

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