Document Detail


The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH.
MedLine Citation:
PMID:  22145625     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  166     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-09     Completed Date:  2012-10-10     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  981-90     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201-1075, USA.
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MeSH Terms
Descriptor/Qualifier:
Bronchi / 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:
AR007592/AR/NIAMS NIH HHS; HL087560/HL/NHLBI NIH HHS; HL108071/HL/NHLBI NIH HHS; R01 AG041265/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
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
Comments/Corrections

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