{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:04:42Z","timestamp":1791288282101,"version":"4.3.0"},"reference-count":69,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,5]]},"abstract":"\n Abstract<\/jats:title>\n \n In neocortical layer\u20105 pyramidal neurons, the action potential (AP) is generated in the axon initial segment (AIS) when the membrane potential (\n V<\/jats:italic>\n m<\/jats:sub>\n ) reaches the threshold for activation of the voltage\u2010gated Na\n +<\/jats:sup>\n channels (VGNCs) Na\n v<\/jats:sub>\n 1.2 and Na\n v<\/jats:sub>\n 1.6. Yet, whereas these VGNCs are known to differ in spatial distribution along the AIS and in biophysical properties, our understanding of the functional differences between the two channels remains elusive. Here, using ultrafast Na\n +<\/jats:sup>\n ,\n V<\/jats:italic>\n m<\/jats:sub>\n and Ca\n 2+<\/jats:sup>\n imaging in combination with partial block of Na\n v<\/jats:sub>\n 1.2 by the peptide G\n 1<\/jats:sup>\n G\n 4<\/jats:sup>\n \u2010huwentoxin\u2010IV, we demonstrate an exclusive role of Na\n v<\/jats:sub>\n 1.2 in shaping the generating AP. Precisely, we show that selective block of \u223c30% of Na\n v<\/jats:sub>\n 1.2 widens the AP in the distal part of the AIS and we demonstrate that this effect is due to a loss of activation of BK Ca\n 2+<\/jats:sup>\n \u2010activated K\n +<\/jats:sup>\n channels (CAKCs). Indeed, Ca\n 2+<\/jats:sup>\n influx via Na\n v<\/jats:sub>\n 1.2 activates BK CAKCs, determining the amplitude and the early phase of repolarization of the AP in the AIS. By using control experiments using 4,9\u2010anhydrotetrodotoxin, a moderately selective inhibitor of Na\n v<\/jats:sub>\n 1.6, we concluded that the Ca\n 2+<\/jats:sup>\n influx shaping the early phase of the AP is exclusive of Na\n v<\/jats:sub>\n 1.2. Hence, we mimicked this result with a neuron model in which the role of the different ion channels tested reproduced the experimental evidence. The exclusive role of Na\n v<\/jats:sub>\n 1.2 reported here is important for understanding the physiology and pathology of neuronal excitability.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n We optically analysed the action potential generated in the axon initial segment of mouse layer\u20105 neocortical pyramidal neurons and its associated Na\n +<\/jats:sup>\n and Ca\n 2+<\/jats:sup>\n currents using ultrafast imaging techniques.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We found that partial selective block of the voltage\u2010gated Na\n +<\/jats:sup>\n channel Na\n v<\/jats:sub>\n 1.2, produced by a recently developed peptide, widens the shape of the action potential in the distal part of the axon initial segment.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We demonstrate that this effect is due to a reduction of the Ca\n 2+<\/jats:sup>\n influx through Na\n v<\/jats:sub>\n 1.2 that activates BK Ca\n 2+<\/jats:sup>\n \u2010activated K\n +<\/jats:sup>\n channels.\n <\/jats:p>\n <\/jats:list-item>\n \n To validate our conclusions, we generated a neuron model that reproduces the ensemble of our experimental results.<\/jats:p>\n <\/jats:list-item>\n \n \n The present results indicate a specific role of Na\n v<\/jats:sub>\n 1.2 in the axon initial segment for shaping of the action potential during its generation.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp283801","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T03:45:56Z","timestamp":1679456756000},"page":"1957-1979","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Nav1.2 and BK channel interaction shapes the action potential in the axon initial segment"],"prefix":"10.1113","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0685-9505","authenticated-orcid":false,"given":"Luiza","family":"Filipis","sequence":"first","affiliation":[{"name":"University Grenoble Alpes, CNRS, LIPhy Grenoble France"},{"name":"Laboratories of Excellence Ion Channel Science and Therapeutics Valbonne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila Ananda","family":"Bl\u00f6mer","sequence":"additional","affiliation":[{"name":"University Grenoble Alpes, CNRS, LIPhy Grenoble France"},{"name":"Laboratories of Excellence Ion Channel Science and Therapeutics Valbonne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Montnach","sequence":"additional","affiliation":[{"name":"Laboratories of Excellence Ion Channel Science and Therapeutics Valbonne France"},{"name":"Nantes Universit\u00e9, CNRS, INSERM, l'Institut du Thorax Nantes 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