In the present review, we discuss the proton-sensing mechanisms, focusing on proton-sensing ionotropic receptors, such as transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs), and metabotropic ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein-coupled receptors (GPCRs), in the airway inflammation and AHR in asthma and respiratory diseases.
Recent studies suggest that OGR1-family GPCRs, including OGR1 (GPR68), GPR4, and T cell-death associated gene 8 (TDAG8 or GPR65), also sense extracellular protons and, thereby, stimulates a variety of cellular activities through several types of G proteins [18-21] (Figure 1).
In ASM cells, OGR1 is expressed at by far the highest levels among proton-sensing gPcRs .
The role of OGR1 in AHR is supported by recent findings with RGS2- and RGS5-deficient mice .
Knockdown of OGR1 and [G.sub.q] expression with small interfering RNAs inhibited acidification-induced increases in [[Ca.sup.2+].sub.i] and mucin production.
Mouse DCs express OGR1family receptors, including OGR1; the functional expression of OGR1 was confirmed by the extracellular acidic pH- and OGR1-dependent increase in [[[Ca.sup.2+]].sub.i].
The findings of the expression of proton-sensing OGR1 in DC, a critical cell for antigen recognition and its presentation to T cells, and the involvement of OGR1 in the DC migration process  suggest participation of OGR1 in the pathophysiology of allergic asthma.
Finally, it should be noted that acidic pH modulates DCs leading to Th1 polarization in humans as described , which contrasts with the role of OGR1 in Th2 polarization in mice.
Cough and bronchoconstriction are activated by severe acidic pH of 4 to 5 and are mainly mediated by pH-sensing channels through sensory neurons, although pH-sensing OGR1 on ASM cells may also be involved in the cell constriction.
List of Abbreviations AHR: Airway hyperresponsiveness ASIC: Acid-sensing ion channel ASM: Airway smooth muscle [[[Ca.sup.2+]].sub.i]: Intracellular [Ca.sup.2+] concentration DC: Dendritic cell ERK: Extracellular signal-regulated kinase GPCR: G protein-coupled receptor [G.sub.q]: [G.sub.q] protein [G.sub.s]: [G.sub.s] protein LPS: Lipopolysaccharide OGR1: Ovarian cancer G protein-coupled receptor 1 PI3K: Phosphatidylinositol 3-kinase RGS: Regulator of G protein signaling TDAG8: T cell-death associated gene 8 TNF-[alpha]: Tumor necrosis factor-[alpha] TRPV1: Transient receptor potential vanilloid-1 PKA: Protein kinase A.
Mogi et al., "Extracellular acidification stimulates IL-6 production and [Ca.sup.2+] mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells," American Journal of Physiology--Lung Cellular and Molecular Physiology, vol.