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.
Highlights
Transient receptor potential vanilloid receptor 4 (TRPV4) is a calcium-permeable non-selective cation channel that can be activated by diverse stimuli including moderate heat, shear stress, endogenous chemicals such as anandamide, arachidonic acid, and its epoxyeicosatrienoic acid metabolites, as well as by a growing number of exogenous chemical ligands such as 4αPDD and GSK1016790A (Vriens et al, 2004; Heller and O’Neil, 2007; Nilius and Voets, 2013)
Previous studies showed that the commonly used TRPV4 activator 4α-PDD activates a majority of dorsal root ganglion (DRG) neurons, a recent study questioned the specificity of 4α-PDD and concluded that its effect on DRG neurons is independent of TRPV4 activation (Alexander et al, 2013)
At both 20 and 40 μg/kg, GSK1016790A evoked a significant decrease in arterial blood pressure, and increase in heart rate (Figure 1; Table 1)
Summary
Transient receptor potential vanilloid receptor 4 (TRPV4) is a calcium-permeable non-selective cation channel that can be activated by diverse stimuli including moderate heat, shear stress, endogenous chemicals such as anandamide, arachidonic acid, and its epoxyeicosatrienoic acid metabolites, as well as by a growing number of exogenous chemical ligands such as 4αPDD and GSK1016790A (Vriens et al, 2004; Heller and O’Neil, 2007; Nilius and Voets, 2013). Growing evidence has shown that TRPV4 is involved in numerous physiological functions including body osmoregulation and noxious mechanical and thermal sensation, and mutation in the TRPV4 gene is known to cause skeletal dysplasia and neurodegenerative diseases (Heller and O’Neil, 2007; Nilius and Voets, 2013; Garcia-Elias et al, 2014). That activation of TRPV4 may indirectly enhance the excitability of these neurons and subsequently affect the respiration through chemoreflexes
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