title: Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate.
abstract: 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.
  
  
  
  We hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bonvini
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.affiliation: School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, Australia.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Grace
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: John J
authors.initials: JJ
authors.lastname: Adcock
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wortley
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Dubuis
authors.affiliation: Airway Disease Infection Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Yee-Man
authors.initials: YM
authors.lastname: Ching
authors.affiliation: Afferent Pharmaceuticals, San Mateo, Calif.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Ford
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Fisnik
authors.initials: F
authors.lastname: Shala
authors.affiliation: Respiratory Therapeutic Area-Discovery, R&D Centre, Almirall S.A., Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.affiliation: Respiratory Therapeutic Area-Discovery, R&D Centre, Almirall S.A., Barcelona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Tarrason
authors.affiliation: Respiratory and Allergy Centre, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom. Electronic address: m.belvisi@imperial.ac.uk.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D003371:Cough; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D012137:Respiratory System / Q000294:innervation* / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D050916:TRPV Cation Channels; D000255:Adenosine Triphosphate
keywords: ATP; Transient receptor potential; cough; hypotonicity; ion channels; sensory nerves; vagus