Reference - Detail
| RRC ID | 87956 |
|---|---|
| Author | Bonvini SJ, Birrell MA, Grace MS, Maher SA, Adcock JJ, Wortley MA, Dubuis E, Ching YM, Ford AP, Shala F, Miralpeix M, Tarrason G, Smith JA, Belvisi MG. |
| Title | Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate. |
| Journal | J Allergy Clin Immunol |
| Abstract |
BACKGROUND:Sensory 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. OBJECTIVE:We hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung. METHODS:We 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. RESULTS:Here 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. CONCLUSION:This 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. |
| Volume | 138(1) |
| Pages | 249-261.e12 |
| Published | 2016-7-1 |
| DOI | 10.1016/j.jaci.2015.10.044 |
| PII | S0091-6749(15)01733-9 |
| PMID | 26792207 |
| PMC | PMC4929136 |
| MeSH | Adenosine Triphosphate / metabolism* Animals Calcium Signaling Cough Dose-Response Relationship, Drug Guinea Pigs Male Mice Mice, Knockout Nerve Fibers, Myelinated / drug effects Nerve Fibers, Myelinated / metabolism Neurons, Afferent / drug effects Neurons, Afferent / metabolism* Nodose Ganglion / cytology Nodose Ganglion / drug effects Nodose Ganglion / metabolism Purinergic P2X Receptor Antagonists / pharmacology Respiratory System / innervation* Respiratory System / metabolism* TRPV Cation Channels / agonists TRPV Cation Channels / metabolism* Vagus Nerve / drug effects Vagus Nerve / physiology |
| IF | 10.228 |
| Resource | |
| Mice | RBRC01939 |