TRP channels in airway sensory nerves

Abstract

Transient Receptor Potential (TRP) channels expressed in specific subsets of airway sensory nerves function as transducers and integrators of a diverse range of sensory inputs including chemical, mechanical and thermal signals. These TRP sensors can detect inhaled irritants as well as endogenously released chemical substances. They play an important role in generating the afferent activity carried by these sensory nerves and regulating the centrally mediated pulmonary defense reflexes. Increasing evidence reported in recent investigations has revealed important involvements of several TRP channels (TRPA1, TRPV1, TRPV4 and TRPM8) in the manifestation of various symptoms and pathogenesis of certain acute and chronic airway diseases. This mini-review focuses primarily on these recent findings of the responses of these TRP sensors to the biological stresses emerging under the pathophysiological conditions of the lung and airways.

Keywords: Airway; C-fiber; Lung; Respiratory disease; Transient receptor potential channel; Vagus.

Fig. 1.. Co-expression of TRPV1 and TRPA1 in airway sensory neurons and a comparison of neural and cough responses to their respective agonists.

A: Single cell RT-PCR of TRPV1+ (top) and TRPV1− (bottom) mouse jugular/nodose cells retrogradely labelled from the lung and airways. Samples in which the reverse transcriptase was omitted (‘−’) served as negative control. cDNA obtained from a whole jugular/nodose ganglion served as positive control (‘+’); B: bath solution was used as a template. B: Effect of cinnamaldehyde and capsaicin, selective agonists of TRPA1 and TRPV1, respectively, on intracellular [Ca2+]_free (expressed as 352/380 ratio) in dissociated DiI-labelled jugular/nodose neurons from mouse lung. C: Responses of pulmonary C-fibers activity to intravenous injections (dashed line) of allyl isothiocyanate (AITC; ave 6×10⁻⁶ mol/kg), a selective agonist of TRPA1, and capsaicin (Cap; ave 1.6×10⁻⁹ mol/kg) in anesthetized rats. Note that the potency of the stimulatory effect of Cap on bronchopulmonary C-fibers is >1000-fold higher than that of AITC. D: Time course of the cough induced by inhalation of AITC and capsaicin (paired study, n=9) in awake guinea pigs. Note that increasing the concentration of AITC from 3 mM to 10 mM did not further increase cough frequency, indicating that the maximally effective concentration of AITC was attained; AITC (10 mM) was significantly less effective in inducing cough than capsaicin (50 μM); *, P<0.05, Cap vs AITC. Data are means ± SEM; n is shown in each panel. (A&B, C and D modified from references 56, 70 and 86, respectively)

Fig. 2.. Synergistic effect of simultaneous activations of TRPA1 and TRPV1 channels in pulmonary sensory neurons.

A: experimental records illustrating the positive interaction of TRPA1 and TRPV1 channels during control in a jugular neuron (27.4 pF). B: the positive interaction was completely abolished after the same neuron was perfused by Ca²⁺-free ECS for 10 min. C: the positive interaction returned after the same neuron was perfused by regular ECS again for 20 min. D: group data of the responses (n=16) when neurons were perfused with regular ECS (Control) and Ca²⁺-free ECS, respectively. E: in 4 of these 16 neurons, group data were also obtained after the Ca²⁺-free ECS was washed out. Data are means ± SEM. *, significantly (P < 0.05) different from the response to (Cap+AITC). F: hypothesized mechanisms involved in the TRPA1-TRPV1 interaction in pulmonary sensory neurons during airway inflammation. Dashed line depicts an inhibitory pathway. Bk, bradykinin; B₂, bradykinin B₂ receptor; DAG, diacyglycerol; EP, prostanoid EP receptors; IP₃, inositol 1,4,5-triphosphate; LO, lipoxygenase products; NT, neurotrophins; PAR₂, protease-activated receptor-2; PGE₂, prostaglandin E₂; PLC, phospholipase C; PLA₂, phospholipase A₂; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; ROS, reactive oxygen species; Temp, temperature; Trk receptors, tryosine receptor kinase receptors A and B. G: potential physical interaction between TRPA1 and TRPV1 subunits in a heteromeric A1/V1 channel complex; Tmem100, a two-transmembrane adaptor protein. (A-E and F-G are modified from references 71 and 74, respectively)