Activation of TRPV4 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 implicated in numerous physiological and pathological functions. This study aimed to investigate the effect of TRPV4 activation on respiration and to explore the potential involvement of bronchopulmonary sensory neurons. Potent TRPV4 agonist GSK1016790A was injected into right atrium in anesthetized spontaneously breathing rats and the changes in breathing were measured. Patch-clamp recording was performed to investigate the effect of GSK1016790A or another TRPV4 activator 4α-PDD on cultured rat vagal bronchopulmonary sensory neurons. Immunohistochemistry was carried out to determine the TRPV4-expressing cells in lung slices obtained from TRPV4-EGFP mice. Our results showed, that right-atrial injection of GSK1016790A evoked a slow-developing, long-lasting rapid shallow breathing in anesthetized rats. Activation of TRPV4 also significantly potentiated capsaicin-evoked chemoreflex responses. The alteration in ventilation induced by GSK1016790A was abolished by cutting or perineural capsaicin treatment of both vagi, indicating the involvement of bronchopulmonary afferent neurons. The stimulating and sensitizing effects of GSK1016790A were abolished by a selective TRPV4 antagonist GSK2193874 and also by inhibiting cyclooxygenase with indomethacin. Surprising, GSK1016790A or 4α-PDD did not activate isolated bronchopulmonary sensory neurons, nor did they modulate capsaicin-induced inward currents in these neurons. Furthermore, TRPV4 expression was found in alveolar macrophages, alveolar epithelial, and vascular endothelial cells. Collectively, our results suggest that GSK1016790A regulates the respiration through an indirect activation of bronchopulmonary sensory neurons, likely via its stimulation of other TRPV4-expressing cells in the lungs and airways.

Transient receptor potential vanilloid 4 channel regulates vascular endothelial permeability during colonic inflammation in dextran sulphate sodium‐induced murine colitis

“…Additionally, the TRPV4 channel was found to mediate neutrophil activation and acute lung injury (Yin et al, ). We found that TRPV4‐immunopositive cells co‐localized with the macrophage marker F4/80 (Supporting Information Figure S1A), which agrees with previous findings in alveolar macrophages (Gu et al, ). We also detected TRPV4‐ and F4/80‐double labelled cells in the bone marrow (Supporting Information Figure S1B).…”

“…We used 1% DMSO / 20% Captisol (sulfobutyl ether‐β‐cyclodextrin) in saline as the vehicle, as described previously (Willette et al, ). The GSK1016790A dose selected should not affect the cardiovascular system, as demonstrated previously (Pankey et al, ; Gu et al, ).…”

Prenatal nicotinic exposure prolongs superior laryngeal C‐fiber–mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation

“…The primary N/J ganglionic neurons were cultured as reported previously (39). Briefly, after decapitation, the rat head was immediately immersed in ice-cold DMEM/F12 solution, followed by quick extraction of N/J ganglia under a dissecting microscope.…”

Polymodal Sensory Transduction in Mouse Corneal Epithelial Cells

“…Animal handling and experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, with the project also approved by the Institutional Animal Care and Use Committee at the University of Utah. C57BL/6 (C57), TRPV4 −/− , 30 and B6.Cg-Gt(ROSA)26Sortm9(CAGtdTomato) Hze/J (Ai9) in which the LoxP-STOP-LoxP TdTomato construct is knocked in at the Gt(ROSA)26Sor locus (referred to as TRPV1 tdT ) 31 and bacterial artificial chromosome (BAC)-transgenic Tg(TRPV4-EGFP)MT43Gsat mice (referred to as TRPV4 eGFP ) mice 32 were maintained in a pathogen-free facility with a 12-hour light/dark cycle and unrestrained access to food and water. Data were gathered from 1-to 3-month-old male and female animals with no noted gender differences.…”