TRPV4 Agonist GSK1016790A Regulates Respiration through Indirect Activation of Bronchopulmonary Sensory Neurons

Abstract

Transient receptor potential vanilloid receptor 4 (TRPV4) is a calcium-permeable non-selective cation channel that has recently been implicated in numerous physiological functions. In this study, we investigate the ventilatory effect of a novel and potent TRPV4 agonist GSK1016790A and further explore the potential involvement of bronchopulmonary sensory neurons. Our results show: 1) in anesthetized rats, right-atrial injection of GSK1016790A evokes a slow-developing, long-lasting rapid shallow breathing; it also significantly potentiates capsaicin-evoked chemoreflexes; 2) the alteration in ventilation induced by GSK1016790A is prevented by cutting or perineural capsaicin treatment of both vagi, indicating the involvement of bronchopulmonary afferent neuron activation; 3) stimulating and sensitizing effects of GSK1016790A are abolished by TRPV4 antagonist GSK2193874 and also by systemic infusion of COX inhibitor indomethacin; 4) in patch-clamp recordings, GSK1016790A does not activate isolated bronchopulmonary sensory neurons, nor does it modulate capsaicin-evoked TRPV1 current in these neurons; and 5) abundant TRPV4 expression is found in alveolar macrophages as well as in vascular endothelial and alveolar epithelial cells. Collectively, our results suggest that GSK1016790A regulates respiration through an indirect activation of bronchopulmonary sensory neurons, likely via its stimulation of other TRPV4 expressing cells in lungs and airways. (Funded by Medcen Community Health Foundation, Mercer University School of Medicine and NIGMS)