Luiza Filipis, Laila Ananda Blömer, Jérôme Montnach, Gildas Loussouarn, Michel De Waard and Marco Canepari (2023) Nav1.2 and BK channel interaction shapes the action potential in the axon initial segment. J Physiol 601: 1957–1979.
1University Grenoble Alpes, CNRS, LIPhy, Grenoble, France
2Laboratories of Excellence, Ion Channel Science and Therapeutics, Valbonne, France
3Nantes Université, CNRS, INSERM, l’Institut du Thorax, Nantes, France
4Institut National de la Santé et Recherche Médicale, Paris, France
In neocortical layer-5 pyramidal neurons, the action potential (AP) is generated in the axon initial segment (AIS) when the membrane potential (V) reaches the threshold for activation of the voltage-gated Na channels (VGNCs) Na1.2 and Na1.6. 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, V and Ca imaging in combination with partial block of Na1.2 by the peptide GG-huwentoxin-IV, we demonstrate an exclusive role of Na1.2 in shaping the generating AP. Precisely, we show that selective block of ∼30% of Na1.2 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-activated K channels (CAKCs). Indeed, Ca influx via Na1.2 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-anhydrotetrodotoxin, a moderately selective inhibitor of Na1.6, we concluded that the Ca influx shaping the early phase of the AP is exclusive of Na1.2. 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 Na1.2 reported here is important for understanding the physiology and pathology of neuronal excitability.
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