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Most of the nine mammalian VGSC subtypes are expressed in nociceptors, but predominantly, three are linked to several human pain syndromes: while Nav1.7 is suggested to be a (sub-)threshold channel, Nav1.8 is thought to support the fast AP upstroke. Nav1.9, as it produces large persistent currents, is attributed a role in determining the resting membrane potential. We characterized the gating of Nav1.1\u2013Nav1.3 and Nav1.5\u2013Nav1.9 in manual patch clamp with a focus on the AP subthreshold depolarization phase. Nav1.9 exhibited the most hyperpolarized activation, while its fast inactivation resembled the depolarized inactivation of Nav1.8. For some VGSCs (e.g., Nav1.1 and Nav1.2), a positive correlation between ramp current and window current was detected. Using a modified Hodgkin\u2013Huxley model that accounts for the time needed for inactivation to occur, we used the acquired data to simulate two nociceptive nerve fiber types (an A\u03b4- and a mechano-insensitive C-nociceptor) containing VGSC conductances according to published human RNAseq data. Our simulations suggest that Nav1.9 is supporting both the AP upstroke and its shoulder. A reduced threshold for AP generation was induced by enhancing Nav1.7 conductivity or shifting its activation to more hyperpolarized potentials, as observed in Nav1.7-related pain disorders. Here, we provide a comprehensive, comparative functional characterization of VGSCs relevant in nociception and describe their gating with Hodgkin\u2013Huxley\u2013like models, which can serve as a tool to study their specific contributions to AP shape and sodium channel\u2013related diseases.<\/jats:p>","DOI":"10.1085\/jgp.202313526","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T02:20:33Z","timestamp":1734574833000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials"],"prefix":"10.1085","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6691-0045","authenticated-orcid":true,"given":"Phil Alexander","family":"K\u00f6ster","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04xfq0f34","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for 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