title: Transient receptor potential ankyrin 1 receptor activation in vitro and in vivo by pro-tussive agents: GRC 17536 as a promising anti-tussive therapeutic.
abstract: 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.
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Mukhopadhyay
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Abhay
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Sarika
authors.initials: S
authors.lastname: Aranake
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Karnik
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Shetty
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Thorat
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Indraneel
authors.initials: I
authors.lastname: Ghosh
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Wale
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Bhosale
authors.affiliation: Biological Research, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai, Maharashtra, India.
authors.forename: Neelima
authors.initials: N
authors.lastname: Khairatkar-Joshi
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D019343:Citric Acid / Q000494:pharmacology; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D051193:Toll-Like Receptors / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D000996:Antitussive Agents; D015220:Calcium Channels; D008024:Ligands; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D051193:Toll-Like Receptors; D050051:Transient Receptor Potential Channels; D019343:Citric Acid; D002118:Calcium