Extracellular acidification stimulates IL-6 production and Ca<sup>2+</sup>mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells

Ichimonji, Isao; Tomura, Hideaki; Mogi, Chihiro; Sato, Kōichi; Aoki, Hiroaki; Hisada, Takeshi; Dobashi, Kunio; Ishizuka, Tamotsu; Mori, Masataka; Okajima, Fumikazu

doi:10.1152/ajplung.00415.2009

Cited by 84 publications

(91 citation statements)

References 55 publications

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“…Ichimonji et al demonstrated in human airway smooth muscle cells that GPR68 mediated extracellular acidification-induced production of pro-inflammatory cytokine IL-6 and increased intracellular Ca 2+ concentration. 64 The same group also found that extracellular acidification of pH 6.3 induced the expression of CTGF, which was involved in the formation of extracellular matrix proteins and associated with airway remodeling, through the GPR68/G q/11 /IP 3 /Ca 2+ pathway. 65 Furthermore, Saxena et al demonstrated that GPR68 receptor mediated airway smooth muscle cell contraction in an acidic extracellular environment.…”

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

confidence: 93%

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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: Role For the Ph-sensing Gpcrs In The Respiratory Systemmentioning

confidence: 93%

“…31 N/A Regulates gene expression and airway smooth muscle cell contraction. [64][65][66][67] GPR68-null mice are resistant to asthma. 68 Skeletal inhibits osteoclastic bone resorption; relative bone density is reduced in GPR65-null mice.…”

Section: Respiratorymentioning

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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“…TDAG8, as well as GPR4, exhibited transforming activities when ectopically overexpressed in immortalized cell lines (Sin et al, 2004). Furthermore, the proton-sensing GPCRs have been shown to regulate immune cell function and inflammatory responses (Ichimonji et al, 2010;Mogi et al, 2009;Onozawa et al, 2011). These observations suggest that the proton-sensing GPCRs may represent novel targets for cancer treatment, inflammation inhibition, and chemoprevention.…”

Section: Molecular Targeting Of Acidosis-related Pathwaysmentioning

confidence: 97%

Targeting Tumor Microenvironments for Cancer Prevention and Therapy

Yang¹,

Castellone²,

Dong³

2012

Cancer Prevention - From Mechanisms to Translational Benefits

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“…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%

“…Most of previous studies on the role of OGR1 were observed at pathophysiological acidic pH of less than pH 7.0 [39]. For example, COX-2 expression and PGE 2 production in osteoclasts [43] and IL-6 and connective tissue growth factor (CTGF) production in airway smooth muscle cells [47,48] in response to acidic pH are observed at pH 6.8 to 6.3. The activation of OGR1 at neutral pH 7.4, however, is not unusual because a remarkable activation of OGR1 at pH 7.4 is observed in CHO cells and in HEK293 cells, in which OGR1 expression was forced [19,62].…”

Section: In Vivo Analysismentioning

confidence: 99%

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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Extracellular acidification stimulates IL-6 production and Ca²⁺mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells

Abstract: . Extracellular acidification stimulates IL-6 production and Ca 2ϩ mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells.

Cited by 84 publications

References 55 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

Targeting Tumor Microenvironments for Cancer Prevention and Therapy

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

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Extracellular acidification stimulates IL-6 production and Ca2+mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells

Abstract: . Extracellular acidification stimulates IL-6 production and Ca 2ϩ mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells.

Cited by 84 publications

References 55 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

Targeting Tumor Microenvironments for Cancer Prevention and Therapy

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

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Extracellular acidification stimulates IL-6 production and Ca²⁺mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells