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Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate
- Source :
- The Journal of Allergy and Clinical Immunology
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Male
Pathology
NCBI, National Center for Biotechnology Information
Respiratory System
vagus
Nerve Fibers, Myelinated
CV, Conduction velocity
Transient receptor potential channel
Mice
hypotonicity
0302 clinical medicine
Adenosine Triphosphate
cough
Medicine
Immunology and Allergy
Mice, Knockout
ion channels
Nodose Ganglion
Vagus Nerve
Px1, Pannexin 1
medicine.anatomical_structure
Nociceptor
TRPV4, Transient receptor potential cation channel, subfamily V, member 4
Mechanisms of Allergy and Clinical Immunology
TRP, Transient receptor potential
Sensory nerve
[Ca2+]i, Intracellular free calcium
TRPV4
DiI, 1,1′-Dioctacetyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate
ECS, Extracellular solution
medicine.medical_specialty
Purinergic P2X Receptor Antagonists
sensory nerves
Guinea Pigs
Immunology
TRPV Cation Channels
COPD, Chronic obstructive pulmonary disease
4α-PDD, 4α Phorbol 12,13-didecanoate
03 medical and health sciences
RAR, Rapidly adapting stretch receptor
Animals
Calcium Signaling
Neurons, Afferent
K50, 50 mmol/L Potassium chloride solution
Dose-Response Relationship, Drug
business.industry
DMSO, Dimethyl sulfoxide
AUC, Area under the curve
Vagus nerve
ATP
030104 developmental biology
030228 respiratory system
Transient receptor potential
Reflex
business
Neuroscience
αβ-MeATP, αβ-Methylene-ATP
Subjects
Details
- ISSN :
- 00916749
- Volume :
- 138
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Allergy and Clinical Immunology
- Accession number :
- edsair.doi.dedup.....49a1c1db7c4db241ca4310008196f321
- Full Text :
- https://doi.org/10.1016/j.jaci.2015.10.044