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Mutations in the genes encoding Navs can lead to severe inherited diseases, and some of these so-called channelopathies show temperature-sensitive phenotypes, for example, paramyotonia congenita, Brugada syndrome, febrile seizure syndromes, and inherited pain syndromes like erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Nevertheless, most investigations of mutation-induced gating effects have been conducted at room temperature, and thus the role of cooling or warming in channelopathies remains poorly understood. Here, we investigated the temperature sensitivity of four Nav subtypes: Nav1.3, Nav1.5, Nav1.6, and Nav1.7, and two mutations in Nav1.7 causing IEM (Nav1.7\/L823R) and PEPD (Nav1.7\/I1461T) expressed in cells of the human embryonic kidney cell line using an automated patch clamp system. Our experiments at 15\u00b0C, 25\u00b0C, and 35\u00b0C revealed a shift of the voltage dependence of activation to more hyperpolarized potentials with increasing temperature for all investigated subtypes. Nav1.3 exhibited strongly slowed inactivation kinetics compared with the other subtypes that resulted in enhanced persistent current, especially at 15\u00b0C, indicating a possible role in cold-induced hyperexcitability. Impaired fast inactivation of Nav1.7\/I1461T was significantly enhanced by a cooling temperature of 15\u00b0C. The subtype-specific modulation as well as the intensified mutation-induced gating changes stress the importance to consider temperature as a regulator for channel gating and its impact on cellular excitability as well as disease phenotypes.<\/jats:p>","DOI":"10.1085\/jgp.202213312","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T02:20:56Z","timestamp":1688610056000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents"],"prefix":"10.1085","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4326-1417","authenticated-orcid":true,"given":"Sophia","family":"Kriegeskorte","sequence":"first","affiliation":[{"name":"University Hospital 1 , , , Aachen, Germany"},{"id":[{"id":"https:\/\/ror.org\/04xfq0f34","id-type":"ROR","asserted-by":"publisher"}],"name":"RWTH Aachen University 1 , , , Aachen, Germany"},{"name":"Institute of Neurophysiology 1 , , , Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raya","family":"Bott","sequence":"additional","affiliation":[{"name":"University Hospital 1 , , , Aachen, Germany"},{"id":[{"id":"https:\/\/ror.org\/04xfq0f34","id-type":"ROR","asserted-by":"publisher"}],"name":"RWTH Aachen University 1 , , , Aachen, Germany"},{"name":"Institute of Neurophysiology 1 , , , Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0184-8879","authenticated-orcid":true,"given":"Martin","family":"Hampl","sequence":"additional","affiliation":[{"name":"Nanion Technologies GmbH 2 , M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-6160","authenticated-orcid":true,"given":"Alon","family":"Korngreen","sequence":"additional","affiliation":[{"name":"Bar Ilan University 3 The Leslie and Susan Gonda multidisciplinary Brain Research Center, , Ramat Gan, Israel"},{"name":"Bar Ilan University 4 The Mina and Everard Goodman Faculty of Life Sciences, , Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0130-110X","authenticated-orcid":true,"given":"Ralf","family":"Hausmann","sequence":"additional","affiliation":[{"name":"University Hospital 5 , , , Aachen, Germany"},{"id":[{"id":"https:\/\/ror.org\/04xfq0f34","id-type":"ROR","asserted-by":"publisher"}],"name":"RWTH Aachen University 5 , , , Aachen, Germany"},{"name":"Institute of Clinical Pharmacology 5 , , , Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6319-6272","authenticated-orcid":true,"given":"Angelika","family":"Lampert","sequence":"additional","affiliation":[{"name":"University Hospital 1 , , , Aachen, Germany"},{"id":[{"id":"https:\/\/ror.org\/04xfq0f34","id-type":"ROR","asserted-by":"publisher"}],"name":"RWTH Aachen University 1 , , , Aachen, Germany"},{"name":"Institute of Neurophysiology 1 , , , Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,8,2]]},"reference":[{"key":"2023080214511478500_bib1","doi-asserted-by":"publisher","first-page":"121","DOI":"10.3389\/fphar.2013.00121","article-title":"A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2","volume":"4","author":"Abdelsayed","year":"2013","journal-title":"Front. 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