The G protein-coupled receptor OGR1 mediates diverse signaling and contraction of airway smooth muscle in response to small reductions in extracellular pH.
Br J Pharmacol. 2011 Dec 6;
Authors: Saxena H, Deshpande DA, Tiegs BC, Yan H, Battafarano RJ, Burrows WM, Damera G, Panettieri RA, Dubose TD, An SS, Penn RB
Abstract
Background and Purpose.? Previous studies have linked a reduction of pH in the 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 capable of mediating airway contraction in response to reductions in airway pH to values of < pH 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. Experimental Approach.? Intracellular signaling events stimulated by ?pHo in cultured human ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using Magnetic Twisting Cytometry. Expression of putative proton-sensing G protein-coupled receptors (GPCRs) in ASM was assessed by real-time PCR. The role of OGR1 in acid-induced ASM signaling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. Key Results.? ASM cells responded to incremental reductions in pHo (from pH 8.0-6.8) by activating multiple signaling pathways, involving p42/p44, Akt, 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 signaling (excepting Akt 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 signaling and mediation of 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.
PMID: 22145625 [PubMed – as supplied by publisher]
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