Positive Interaction between TRPA1 and TRPV1 Channels in Rat Vagal Bronchopulmonary Sensory Neurons

Abstract

Both TRPA1 and TRPV1 are selectively and abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. They can be either activated or sensitized by a number of endogenous inflammatory mediators such as H+, ROS, bradykinin, protanoids, etc. As such, it is highly probable that concurrent activation of these two receptors can occur during airway inflammatory reaction. A recent study has demonstrated a distinct synergistic effect of simultaneous activation of TRPA1 and TRPV1 in vagal pulmonary C-fiber afferents in anesthetized rats (Lin et al., JAP, 2014), but its underlying mechanism and whether this action occurred directly at the sensory neurons were not known. This study was carried out to answer these questions in isolated nodose and jugular pulmonary sensory neurons. Using the perforated patch-clamp recording technique, our results showed: 1) The current density evoked by a combination of low concentrations of allyl isothiocyanate (AITC, a TRPA1 activator; 30 µM) and capsaicin (Cap, a TRPV1 activator; 0.1-0.3 µM) was 233% of the mathematical sum of the responses to AITC and Cap when they were administered separately at the same concentration and duration (4 sec) in the same neurons. 2) The positive interaction was absent when either AITC or Cap was replaced by another chemical activator of these neurons (e.g., ATP or phenylbiguanide). 3) This synergistic effect was completely blocked when Ca2+ was removed from the extracellular solution. 4) Application of AITC alone immediately preceding Cap also significantly augmented the Cap-evoked current, whereas reversing the order did not potentiate the response to AITC. In conclusion, a positive interaction occurs directly in vagal pulmonary sensory neurons between TRPA1 and TRPV1 when both are activated, and the extracellular Ca2+ plays an important role in this action.