| The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH. | |
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MedLine Citation:
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PMID: 22145625 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Previous studies have linked a reduction in pH in airway, caused by either environmental factors, microaspiration of gastric acid or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown to mediate airway contraction in response to reductions in airway pH to < 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. EXPERIMENTAL APPROACH: Intracellular signalling events stimulated by reduced pHo in human cultured ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using magnetic twisting cytometry. The expression of putative proton-sensing GPCRs in ASM was assessed by real-time PCR. The role of ovarian cancer G protein-coupled receptor 1 (OGR1 or GPR68) in acid-induced ASM signalling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. KEY RESULTS: ASM cells responded to incremental reductions in pHo (from pH 8.0 to pH 6.8) by activating multiple signalling pathways, involving p42/p44, PKB, PKA and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar 'dose'-dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signalling (with the exception of PKB activation) and contraction were significantly attenuated by knockdown of OGR1. CONCLUSIONS AND IMPLICATIONS: These studies reveal OGR1 to be a physiologically relevant GPCR in ASM cells, capable of pleiotropic signalling and mediating contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases. |
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Authors:
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H Saxena; D A Deshpande; B C Tiegs; H Yan; R J Battafarano; W M Burrows; G Damera; R A Panettieri; T D Dubose; S S An; R B Penn |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of pharmacology Volume: 166 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-05-09 Completed Date: 2012-10-10 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 981-90 Citation Subset: IM |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201-1075, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Bronchi
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cytology,
drug effects Cell Culture Techniques Cells, Cultured Cyclic AMP / metabolism Cyclooxygenase Inhibitors / pharmacology Dose-Response Relationship, Drug Extracellular Fluid / chemistry* Humans Hydrochloric Acid / pharmacology Hydrogen-Ion Concentration Indomethacin / pharmacology Muscle Contraction / drug effects* Muscle, Smooth / cytology, drug effects, metabolism* Real-Time Polymerase Chain Reaction Receptors, G-Protein-Coupled / metabolism, physiology* Signal Transduction / drug effects, physiology* Trachea / cytology, drug effects |
| Grant Support | |
ID/Acronym/Agency:
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AR007592/AR/NIAMS NIH HHS; HL087560/HL/NHLBI NIH HHS; HL108071/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cyclooxygenase Inhibitors; 0/GPR68 protein, human; 0/Receptors, G-Protein-Coupled; 53-86-1/Indomethacin; 60-92-4/Cyclic AMP; 7647-01-0/Hydrochloric Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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