Cough is a protective reflex action that helps clear the respiratory tract which is continuously exposed to airborne environmental irritants. However,
chronic cough presents itself as a disease in its own right and despite its global occurrence; the molecular mechanisms responsible for
cough are not completely understood. Transient receptor potential ankyrin1 (TRPA1) is robustly expressed in the neuronal as well as non-neuronal cells of the respiratory tract and is a sensor of a wide range of environmental irritants. It is fast getting acceptance as a key
biological sensor of a variety of pro-tussive agents often implicated in miscellaneous
chronic cough conditions. In the present study, we demonstrate in vitro direct functional activation of TRPA1 receptor by
citric acid which is routinely used to evoke
cough in preclinical and clinical studies. We also show for the first time that a potent and selective TRPA1 antagonist GRC 17536 inhibits
citric acid induced cellular Ca(+2) influx in TRPA1 expressing cells and the
citric acid induced
cough response in guinea pigs. Hence our data provides a mechanistic link between TRPA1 receptor activation in vitro and
cough response induced in vivo by
citric acid. Furthermore, we also show evidence for TRPA1 activation in vitro by the TLR4, TLR7 and TLR8
ligands which are implicated in bacterial/respiratory virus pathogenesis often resulting in
chronic cough. In conclusion, this study highlights the potential utility of TRPA1 antagonist such as GRC 17536 in the treatment of miscellaneous
chronic cough conditions arising due to diverse causes but commonly driven via TRPA1.