Transient receptor potential cation channel, subfamily V, member 4 and airway, sensory afferent activation: role of adenosine triphosphate
File(s)
Accepted version
Accepted version
Author(s)
Belvisi, MG
Type
Journal Article
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.
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.
Date Issued
2016-07-01
Date Acceptance
2015-10-28
Citation
Journal of Allergy and Clinical Immunology, 2016, 138 (1), pp.249-261.e12
ISSN
1097-6825
Publisher
Elsevier
Start Page
249
End Page
261.e12
Journal / Book Title
Journal of Allergy and Clinical Immunology
Volume
138
Issue
1
Copyright Statement
© 2015 The Authors. Published by Elsevier Inc. on behalf of the American Academy
of Allergy, Asthma & Immunology. This is an open access article under the CC BYNC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.jaci.2015.10.044
of Allergy, Asthma & Immunology. This is an open access article under the CC BYNC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.jaci.2015.10.044
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Imperial Innovations Ltd
North West Lung Centre
Grant Number
MR/K020293/1
PO 75415839
7112
n/a
Subjects
ATP
Transient receptor potential
cough
hypotonicity
ion channels
sensory nerves
vagus
Allergy
1107 Immunology
Publication Status
Published
Date Publish Online
2016-01-11