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Purinergic 2 receptors (P2X) belong to a class of adenosine triphosphate (ATP)-gated non-selective cation channels that also play an important role in cough hypersensitivity. Nevertheless, little is known about the interaction between them for cough hypersensitivity. The present study was designed to clarify the roles of TRPV4 and ATP-P2X receptors in cough hypersensitivity, and to explore the possible involvement of ATP-P2X receptors in the development of cough hypersensitivity mediated by TRPV4. Design and Method: This study aims to establish a guinea pig model of citric acid-induced enhanced cough to confirm the effects of the TRPV4-mediated purinergic signaling pathway on cough sensitivity by testing the number of coughs, the release of ATP, and the expressions of P2X and TRPV4 receptors in the tracheal carina and vagal ganglion; recording the activity of cellular currents with the whole-cell patch clamp technique; and detecting changes in intracellular calcium flow in the vagus nerve cells. Results: The number of coughs in the TRPV4 agonist GSK1016790A-treated control group was elevated compared with that in the control group, whereas the number of coughs in the TRPV4 antagonist HC067047-treated model group was significantly reduced compared with that in the chronic cough group. When the individuals in the chronic cough group were treated with A317491, PSB12062, and A804598 (P2X3,4,7 antagonists), the number of coughs was significantly decreased. This suggests that TRPV4 and P2X3, P2X4, and P2X7 receptors have an effect on cough hyper-responsiveness in guinea pigs with chronic cough. Enzyme-linked immunosorbent assay results suggested that TRPV4 antagonist and P2X3,4,7 antagonist could differentially reduce the levels of inflammatory factor SP and CGRP in alveolar lavage fluid, and TRPV4 antagonist could reduce the ATP content in the alveolar lavage fluid of guinea pigs in the model. Western blot and immunohistochemistry results showed that, in the tracheal carina and vagal ganglion, the TRPV4 and P2X3,4,7 expression was elevated in the chronic cough group compared with the control group, and could be significantly inhibited by TRPV4 antagonist. Vagus ganglion neurons were isolated, cultured, identified, and subjected to whole-cell membrane clamp assay. When ATP was given extracellularly, a significant inward current was recorded in the examined cells of individuals in the chronic cough and control groups, and the inward current induced by ATP was higher in the chronic cough group relative to the control group. This inward current (IATP) was differentially blocked by P2X3, P2X4, and P2X7 antagonists. Further studies revealed that TRPV4 agonists potentiated ATP-activated currents, and the potentiated currents could still be inhibited by P2X3, P2X4, and P2X7 receptor antagonists, whereas TRPV4 inhibitors partially blocked ATP-activated currents. It is suggested that TRPV4 affects P2X3, P2X4, and P2X7 receptor-mediated ATP-activated currents. Calcium imaging also showed that TRPV4 agonists induced different degrees of calcium inward currents in the vagal neurons of the chronic cough and the control group, and the calcium inward currents were more significant in the model group. Conclusions: The TRPV4-mediated purinergic signaling pathway was identified to be involved in the development of cough hypersensitivity in guinea pigs with chronic cough; i.e., TRPV4 can lead to the release of airway epithelial ATP, which can stimulate P2X receptors on the cough receptor, and further activate the sensory afferent nerves in the peripheral airway, leading to increased cough sensitivity.<\/jats:p>","DOI":"10.3390\/biom15020285","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T11:14:41Z","timestamp":1739531681000},"page":"285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Activation of Adenosine Triphosphate-Gated Purinergic 2 Receptor Channels by Transient Receptor Potential Vanilloid Subtype 4 in Cough Hypersensitivity"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9980-7933","authenticated-orcid":false,"given":"Wanzhen","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-2998","authenticated-orcid":false,"given":"Shengyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4375-0499","authenticated-orcid":false,"given":"Tongyangzi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8713-5332","authenticated-orcid":false,"given":"Xianghuai","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1378\/chest.12-0441","article-title":"A prospective, multicenter survey on causes of chronic cough in China","volume":"143","author":"Lai","year":"2013","journal-title":"Chest"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17534666231220817","DOI":"10.1177\/17534666231220817","article-title":"A comparison between a gastroesophageal reflux disease questionnaire-based algorithm and multichannel intraluminal impedance-pH monitoring for the treatment of gastroesophageal reflux-induced chronic cough","volume":"18","author":"Li","year":"2024","journal-title":"Ther. 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