Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate

Abstract

BackgroundSensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored.ObjectiveWe hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung.MethodsWe used guinea pig primary cells, tissue bioassay, in vivo electrophysiology, and a guinea pig conscious cough model to investigate a role for TRPV4 in mediating sensory nerve activation in vagal afferents and the possible downstream signaling mechanisms. Human vagus nerve was used to confirm key observations in animal tissues.ResultsHere we show TRPV4-induced activation of guinea pig airway–specific primary nodose ganglion cells. TRPV4 ligands and hypo-osmotic solutions caused depolarization of murine, guinea pig, and human vagus and firing of Aδ-fibers (not C-fibers), which was inhibited by TRPV4 and P2X3 receptor antagonists. Both antagonists blocked TRPV4-induced cough.ConclusionThis study identifies the TRPV4-ATP-P2X3 interaction as a key osmosensing pathway involved in airway sensory nerve reflexes. The absence of TRPV4-ATP–mediated effects on C-fibers indicates a distinct neurobiology for this ion channel and implicates TRPV4 as a novel therapeutic target for neuronal hyperresponsiveness in the airways and symptoms, such as cough.

The emerging role of transient receptor potential channels in chronic lung disease

“…Both antagonists blocked TRPV4-induced cough, suggesting that TRPV4 releases ATP which activates the Aδ-fibres to induce cough. This study identifies the TRPV4-ATP-P2X3 axis as a driver of airway sensory nerve reflexes such as cough [82]. However, it is still not clear where TRPV4 is expressed in this context, although the identification of P2X3 receptors on airway afferents [83] and a recent clinical trial demonstrating the efficacy of a P2X3 receptor antagonist in treatment-resistant chronic cough patients would support the role of ATP as a driver of the cough reflex [84].…”

“…However, expression studies were performed on whole ganglia rather than single-cell expression studies on isolated neurons, so expression on non-neuronal cells cannot be ruled out. More recently, single-cell expression studies performed on airway-specific neurons from the jugular or nodose ganglia did not yield convincing data relating to TRPV4 mRNA expression in the vagal ganglia [82], but did demonstrate TRPV4-induced activation of guinea pig airway-specific, primary nodose, but not jugular, ganglion cells. In the same study, TRPV4 ligands and hypo-osmotic solutions caused depolarisation of murine, guinea pig and human vagus nerve and firing of Aδ fibres (not C-fibres) which was inhibited by TRPV4 and P2X3 receptor antagonists.…”

“…This effect is thought to be mediated by TRPV4-mediated ATP release from airway smooth muscle, which activates P2X4 receptors on mast cells to release cysteinyl leukotrienes (LT) which activate the Cys LT 1 receptor to evoke contraction [112,134]. Interestingly, many of the functional effects of TRPV4 activation are due to the release of ATP and activation of purinoceptors [8,82,99,134,135] and TRPV4-induced ATP release has been demonstrated in human macrophages, epithelial and smooth muscle cells [99,113,135]. In addition, TRPV4-induced ATP release has been shown to be released via a pannexin 1-dependent mechanism [82,99,135].…”

Cough Hypersensitivity Syndrome: A Few More Steps Forward

“…This “distress signal” is then picked up by sensory neurons through the P2X3 receptor which is then responsible for the promotion of hypersensitivity. A potential trigger for ATP release has been elegantly described in studies using knockout mice where stimulation of TRPV4 produced a long-lasting depolarisation, and this was thought to act through pannexin channels that allow ATP to escape into the extracellular milieu 74. Mechanisms other than ATP release will almost certainly be described since even potent blockers of P2X3 receptors are not totally effective for treating chronic cough 66.…”

Review of the British Thoracic Society Winter Meeting 2017, 6–8 December 2017, London, UK

“…She hypothesised that irritants directly activate transient receptor potential (TRP) ion channels to initiate these sensory reflex events. She highlighted that TRPV4 activation releases ATP which, in turn, acts on P2×3 present on sensory nerves, resulting in the cough reflex 32. The discovery of this axis opens up a completely new therapeutic opportunity for improving symptoms with use of either P2×3 or TRPV4 antagonists 33…”