{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T13:57:07Z","timestamp":1781013427758,"version":"3.54.1"},"reference-count":82,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,22]],"date-time":"2020-06-22T00:00:00Z","timestamp":1592784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1161733"],"award-info":[{"award-number":["1161733"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1181076"],"award-info":[{"award-number":["1181076"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002941","name":"Departamento de Investigaciones Cient\u00edficas y Tecnol\u00f3gicas, Universidad de Santiago de Chile","doi-asserted-by":"publisher","award":["021843PP"],"award-info":[{"award-number":["021843PP"]}],"id":[{"id":"10.13039\/501100002941","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["21161660"],"award-info":[{"award-number":["21161660"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Vicerrector\u00eda de Investigaci\u00f3n Desarrollo e Innovaci\u00f3n Universidad Santiago de Chile (VRIDEI-USACH)","award":["AP-539MM"],"award-info":[{"award-number":["AP-539MM"]}]},{"name":"Centro Basal","award":["AC3E FB0008"],"award-info":[{"award-number":["AC3E FB0008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>TRPM8 is the main molecular entity responsible for cold sensing. This polymodal ion channel is activated by cold, cooling compounds such as menthol, voltage, and rises in osmolality. In corneal cold thermoreceptor neurons (CTNs), TRPM8 expression determines not only their sensitivity to cold, but also their role as neural detectors of ocular surface wetness. Several reports suggest that Protein Kinase C (PKC) activation impacts on TRPM8 function; however, the molecular bases of this functional modulation are still poorly understood. We explored PKC-dependent regulation of TRPM8 using Phorbol 12-Myristate 13-Acetate to activate this kinase. Consistently, recombinant TRPM8 channels, cultured trigeminal neurons, and free nerve endings of corneal CTNs revealed a robust reduction of TRPM8-dependent responses under PKC activation. In corneal CTNs, PKC activation decreased ongoing activity, a key parameter in the role of TRPM8-expressing neurons as humidity detectors, and also the maximal cold-evoked response, which were validated by mathematical modeling. Biophysical analysis indicated that PKC-dependent downregulation of TRPM8 is mainly due to a decreased maximal conductance value, and complementary noise analysis revealed a reduced number of functional channels at the cell surface, providing important clues to understanding the molecular mechanisms of how PKC activity modulates TRPM8 channels in CTNs.<\/jats:p>","DOI":"10.3390\/ijms21124420","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T06:11:02Z","timestamp":1592892662000},"page":"4420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1848-8334","authenticated-orcid":false,"given":"Basti\u00e1n","family":"Rivera","sequence":"first","affiliation":[{"name":"Department of Biology, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile, and Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), 9160000 Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mat\u00edas","family":"Campos","sequence":"additional","affiliation":[{"name":"Department of Biology, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile, and Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), 9160000 Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0332-8098","authenticated-orcid":false,"given":"Patricio","family":"Orio","sequence":"additional","affiliation":[{"name":"Centro Interdisciplinario de Neurociencia de Valpara\u00edso and Instituto de Neurociencia, Facultad de Ciencias, Universidad de Valpara\u00edso, 2360102 Valpara\u00edso, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Madrid","sequence":"additional","affiliation":[{"name":"Department of Biology, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile, and Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), 9160000 Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3856-9019","authenticated-orcid":false,"given":"Mar\u00eda","family":"Pertusa","sequence":"additional","affiliation":[{"name":"Department of Biology, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile, and Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), 9160000 Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrn3784","article-title":"Peripheral thermosensation in mammals","volume":"15","author":"Vriens","year":"2014","journal-title":"Nat. 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