Numerous studies suggest alterations in airway pH contribute to the pathophysiology of obstructive airway diseases. Airway acidification can be caused by exogenous as well as endogenous sources including airway inflammation. Neural mechanisms have been shown capable of mediating acidosis-induced bronchoconstriction, but whether reduced pH in the airway microenvironment has direct effects on airway smooth muscle (ASM) is unknown. We have discovered that ASM expresses OGR1, a member of a unique subfamily of G protein-coupled receptors (GPCRs) proposed to be """"""""proton-sensing."""""""" Preliminary data suggest OGR1 is expressed in ASM and, in response to reductions in extracellular pH, signals in a manner consistent with pro-contractile Gq-coupled GPCRs. Moreover, tracheal rings are observed to contract ex vivo with modest step decreases in buffer pH that parallel the activation profile of OGR1. Because of the complex issues inherent in analysis of the effect of acidosis/pH in integrative systems, we propose to first undertake a careful, restricted analysis of OGR1 signaling and function in human ASM cells, to establish the relevance of ASM OGR1.
Aim 1 will use pharmacological and molecular biology techniques to delineate the signaling events and their requirement for OGR1 in acid-induced signaling and contraction in ASM.
Aim 2 will establish activation of OGR1 in ASM involves direct activation of the receptor by protons, while attempting to exclude any role for acid-activated autocrine or paracrine agents. If successful, these studies will identify a novel signaling pathway in ASM that could play a prominent role in the pathobiology of numerous airways diseases, and provide a solid basis for subsequent integrative studies examining the capacity and relevance of pH regulation of OGR1 in ASM and airway function.
Numerous studies suggest that acidification (reduced pH) of the airway, caused by either environmental sources (air pollution) or from within the lung (aspiration of stomach acid, or via airway inflammation) can cause airway smooth muscle to contract and thereby cause or contribute to diseases such as asthma or chronic obstructive pulmonary disease. We have discovered that airway smooth muscle cells express the receptor OGR1 which has recently been proposed to be activated by acidification/reduced pH. Thus OGR1 represents a novel means by which airway smooth muscle might contract when exposed to environmental or endogenous sources of acid. We propose a comprehensive analysis to clarify the ability of OGR1 to signal and function in human airway smooth muscle cells. Successful completion of these studies will identify a novel mechanism of airway smooth muscle contraction and a new target for therapies for obstructive lung diseases.
|Billington, Charlotte K; Ojo, Oluwaseun O; Penn, Raymond B et al. (2013) cAMP regulation of airway smooth muscle function. Pulm Pharmacol Ther 26:112-20|
|Saxena, H; Deshpande, D A; Tiegs, B C et al. (2012) The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH. Br J Pharmacol 166:981-90|