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

      research-article
      , PhD a , , , PhD a , , , PhD b , , PhD a , , PhD a , , PhD a , , PhD a , , MRes c , , PhD e , , MD a , , PhD f , , PhD f , , PhD d , , PhD a ,
      The Journal of Allergy and Clinical Immunology
      Mosby
      Transient receptor potential, sensory nerves, vagus, cough, ion channels, hypotonicity, ATP, AUC, Area under the curve, [Ca2+]i, Intracellular free calcium, COPD, Chronic obstructive pulmonary disease, CV, Conduction velocity, DiI, 1,1′-Dioctacetyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate, DMSO, Dimethyl sulfoxide, ECS, Extracellular solution, K50, 50 mmol/L Potassium chloride solution, αβ-MeATP, αβ-Methylene-ATP, NCBI, National Center for Biotechnology Information, 4α-PDD, 4α Phorbol 12,13-didecanoate, Px1, Pannexin 1, RAR, Rapidly adapting stretch receptor, TRP, Transient receptor potential, TRPV4, Transient receptor potential cation channel, subfamily V, member 4

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          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.

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          Most cited references43

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          Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.

          The detection of osmotic stimuli is essential for all organisms, yet few osmoreceptive proteins are known, none of them in vertebrates. By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, we cloned cDNAs encoding the vanilloid receptor-related osmotically activated channel (VR-OAC) from the rat, mouse, human, and chicken. This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. In the central nervous system, the channel is expressed in neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. The channel also occurs in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells.
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            • Article: not found

            International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family.

            Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca(2+) and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels.
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              Impaired pressure sensation in mice lacking TRPV4.

              The sensation of pressure, mechanosensation, in vertebrates remains poorly understood on the molecular level. The ion channel TRPV4 is in the TRP family and is a candidate for a mechanosensitive calcium-permeable channel. It is located in dorsal root ganglia. In the present study, we show that disrupting the Trpv4 gene in mice markedly reduced the sensitivity of the tail to pressure and acidic nociception. The threshold to noxious stimuli and the conduction velocity of myelinated nerve responding to stimuli were also impaired. Activation of unmyelinated nerve was undetected. However, the mouse still retained olfaction, taste sensation, and heat avoidance. The TRPV4 channel expressed in vitro in Chinese hamster ovary cells was opened by low pH, citrate, and inflation but not by heat or capsaicin. These data identify the TRPV4 channel as essential for the normal detection of pressure and as a receptor of the high-threshold mechanosensory complex.
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                Author and article information

                Contributors
                Journal
                J Allergy Clin Immunol
                J. Allergy Clin. Immunol
                The Journal of Allergy and Clinical Immunology
                Mosby
                0091-6749
                1097-6825
                1 July 2016
                July 2016
                : 138
                : 1
                : 249-261.e12
                Affiliations
                [a ]Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom
                [c ]Airway Disease Infection Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom
                [b ]School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, Australia
                [d ]Respiratory and Allergy Centre, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom
                [e ]Afferent Pharmaceuticals, San Mateo, Calif
                [f ]Respiratory Therapeutic Area–Discovery, R&D Centre, Almirall S.A., Barcelona, Spain
                Author notes
                []Corresponding author: Maria G. Belvisi, PhD, Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College, Exhibition Road, London SW7 2AZ, United Kingdom.Respiratory Pharmacology GroupAirway Disease SectionNational Heart & Lung InstituteImperial CollegeExhibition RoadLondonSW7 2AZUnited Kingdom m.belvisi@ 123456imperial.ac.uk
                [∗]

                These authors contributed equally to this work.

                Article
                S0091-6749(15)01733-9
                10.1016/j.jaci.2015.10.044
                4929136
                26792207
                bb1c9770-3ba0-40ee-a65e-976d029c25b6
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 31 October 2014
                : 19 October 2015
                : 28 October 2015
                Categories
                Mechanisms of Allergy and Clinical Immunology

                Immunology
                transient receptor potential,sensory nerves,vagus,cough,ion channels,hypotonicity,atp,auc, area under the curve,[ca2+]i, intracellular free calcium,copd, chronic obstructive pulmonary disease,cv, conduction velocity,dii, 1,1′-dioctacetyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate,dmso, dimethyl sulfoxide,ecs, extracellular solution,k50, 50 mmol/l potassium chloride solution,αβ-meatp, αβ-methylene-atp,ncbi, national center for biotechnology information,4α-pdd, 4α phorbol 12,13-didecanoate,px1, pannexin 1,rar, rapidly adapting stretch receptor,trp, transient receptor potential,trpv4, transient receptor potential cation channel, subfamily v, member 4

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