Regulation of acid signaling in rat pulmonary sensory neurons by protease-activated receptor-2.

Airway acidification has been consistently observed in airway inflammatory conditions and is known to cause cardiorespiratory symptoms that are, at least in part, mediated through the activation of bronchopulmonary C fibers and the subsequent reflexes. Protease-activated receptor-2 (PAR(2)) is expressed in a variety of cells in the lung and airways and is believed to play a role in airway inflammation and hyperresponsiveness. This study was carried out to investigate the effect of PAR(2) activation on the acid signaling in rat bronchopulmonary C-fiber sensory neurons. Our RT-PCR results revealed the expression of mRNAs for transient receptor potential vanilloid receptor 1 (TRPV1) and four functional acid-sensing ion channel (ASIC) subunits 1a, 1b, 2a, and 3 in these sensory neurons. Preincubation of SLIGRL-NH(2), a specific PAR(2)-activating peptide, markedly enhanced the Ca(2+) transient evoked by extracellular acidification. Pretreatment with PAR(2) agonists significantly potentiated both acid-evoked ASIC- and TRPV1-like whole cell inward currents. Activation of PAR(2) also potentiated the excitability of these neurons to acid, but not electrical stimulation. In addition, the potentiation of acid-evoked responses was not prevented by inhibiting either PLC or PKC nor was mimicked by activation of PKC. In conclusion, activation of PAR(2) modulates the acid signaling in pulmonary sensory neurons, and the interaction may play a role in the pathogenesis of airway inflammatory conditions, where airway acidification and PAR(2) activation can occur simultaneously.