{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T03:00:09Z","timestamp":1777950009998,"version":"3.51.4"},"reference-count":98,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cyclin-dependent kinase 5 (Cdk5) plays a critical role in pain transmission by phosphorylating key nociceptive proteins. One of its recently identified substrates, the P2X2 subunit, is part of the P2X2\/3 purinergic receptor (P2X2\/3R), which is implicated in nociceptive signaling. However, the specific contribution of Cdk5 to purinergic receptor-mediated pain responses remains unclear. This study aimed to investigate the role of Cdk5 in pain responses elicited by \u03b1,\u03b2-methylene ATP (\u03b1,\u03b2-meATP), an agonist of P2X2\/3R and P2X3R.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Both pharmacological inhibition and genetic loss-of-function approaches were used to assess the role of Cdk5. Calcium (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ) imaging was performed in cultured murine trigeminal ganglion (TG) neurons to characterize \u03b1,\u03b2-meATP-evoked responses. Surface biotinylation assays in HEK293 cells were used to assess P2X2 receptor membrane expression.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , facial pain was induced by injecting \u03b1,\u03b2-meATP into the whisker pad of mice. Behavioral responses were evaluated in conditional Cdk5 knockout mice targeting sensory neurons and in control littermates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In TG neuron cultures, \u03b1,\u03b2-meATP evoked both fast and slow Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transients, which were sensitive to P2X3 or P2X2\/3 channel blockade. Inhibition or genetic loss-of-function of Cdk5 predominantly accelerated the decay of slow responses, with minimal effects on fast responses. In HEK293 cells, Cdk5 activation did not alter the surface expression of P2X2 receptors.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , \u03b1,\u03b2-meATP induced facial pain-like behaviors, including grooming and head flinching, which were significantly reduced in conditional Cdk5 knockout mice compared to controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings indicate that Cdk5 modulates orofacial pain by regulating purinergic receptor-mediated signaling in trigeminal neurons. Specifically, Cdk5 appears to influence the functional properties of P2X2-containing channels, most likely P2X2\/3 heteromeric receptors, without affecting their membrane expression. This modulation of receptor kinetics may underlie the observed changes in nociceptive behavior, highlighting Cdk5 and P2X receptors as a potential target for pain modulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1767160","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T05:32:45Z","timestamp":1777872765000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cdk5 modulates orofacial pain through P2X2\/3 purinergic receptor-mediated signaling in trigeminal neurons"],"prefix":"10.3389","volume":"17","author":[{"given":"Rodrigo","family":"Sandoval","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Science, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicol\u00e1s","family":"Pinto-Pardo","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science, Universidad de Chile","place":["Santiago, Chile"]},{"name":"Dentistry, Department of Dental Sciences, Faculty of Life Sciences, Universidad Vi\u00f1a del Mar","place":["Vi\u00f1a del Mar, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camila","family":"Duran","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricio","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine, Universidad Cat\u00f3lica del Norte","place":["Coquimbo, Chile"]},{"name":"Department of Physiology, Faculty of Biological Sciences, Universidad de Concepci\u00f3n","place":["Concepci\u00f3n, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine, Universidad Cat\u00f3lica del Norte","place":["Coquimbo, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Gonz\u00e1lez-Billault","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science, Universidad de Chile","place":["Santiago, Chile"]},{"name":"Department of Neurosciences, Faculty of Medicine, Universidad de Chile","place":["Santiago, Chile"]},{"name":"Geroscience Center for Brain Health and Metabolism","place":["Santiago, Chile"]},{"name":"The Buck Institute for Research on Aging","place":["Novato, CA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Pertusa","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Chemistry and Biology, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodolfo","family":"Madrid","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Chemistry and Biology, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Coddou","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Medicine, Universidad Cat\u00f3lica del Norte","place":["Coquimbo, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"El\u00edas","family":"Utreras","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/1744-8069-6-59","article-title":"Purinergic receptors are involved in tooth-pulp evoked nocifensive behavior and brainstem neuronal activity","volume":"6","author":"Adachi","year":"2010","journal-title":"Mol. 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