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

• Published in: Journal of allergy and clinical immunology Vol. 138; no. 1; pp. 249 - 261.e12
• Main Authors: Bonvini, Sara J., Birrell, Mark A., Grace, Megan S., Maher, Sarah A., Adcock, John J., Wortley, Michael A., Dubuis, Eric, Ching, Yee-Man, Ford, Anthony P., Shala, Fisnik, Miralpeix, Montserrat, Tarrason, Gema, Smith, Jaclyn A., Belvisi, Maria G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2016; Elsevier Limited; Mosby
• Subjects: Adenosine Triphosphate - metabolism; Allergy and Immunology; Animals; Asthma; ATP; Calcium Signaling; Chronic obstructive pulmonary disease; Cough; Dose-Response Relationship, Drug; Experiments; Genetic engineering; Guinea Pigs; hypotonicity; ion channels; Male; Mechanisms of Allergy and Clinical Immunology; Mice; Mice, Knockout; Nerve Fibers, Myelinated - drug effects; Nerve Fibers, Myelinated - metabolism; Neurons; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Neurosciences; Nodose Ganglion - cytology; Nodose Ganglion - drug effects; Nodose Ganglion - metabolism; Purinergic P2X Receptor Antagonists - pharmacology; Respiratory System - innervation; Respiratory System - metabolism; Rodents; sensory nerves; Transient receptor potential; TRPV Cation Channels - agonists; TRPV Cation Channels - metabolism; vagus; Vagus Nerve - drug effects; Vagus Nerve - physiology; RAR; [Ca2+]i; DiI; DMSO; K50; Px1; hypotonicity; αβ-MeATP; cough; Transient receptor potential; ion channels; sensory nerves; AUC; CV; TRP; ECS; vagus; 4α-PDD; TRPV4; NCBI; ATP; COPD; National Center for Biotechnology Information; 50 mmol/L Potassium chloride solution; Conduction velocity; 1,1′-Dioctacetyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate; Pannexin 1; Area under the curve; Chronic obstructive pulmonary disease; Rapidly adapting stretch receptor; [Ca 2+] i; Transient receptor potential cation channel, subfamily V, member 4; Intracellular free calcium; Dimethyl sulfoxide; 4α Phorbol 12,13-didecanoate; αβ-Methylene-ATP; Extracellular solution
• ISSN: 0091-6749; 1085-8725; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2015.10.044

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.