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 (PAR₂) 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 PAR₂ 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 PAR2-activating peptide, markedly enhanced the Ca ²⁺ transient evoked by extracellular acidification. Pretreatment with PAR₂ agonists significantly potentiated both acid-evoked ASIC- and TRPV1-like whole cell inward currents. Activation of PAR₂ 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 PAR₂ 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 PAR₂ activation can occur simultaneously.