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Nav1.2 and BK channels interaction shapes the action potential in the axon initial segment.

Journal of Physiology 2023 March 23
In neocortical layer-5 pyramidal neurons, the action potential (AP) is generated in the axon initial segment (AIS) when the membrane potential (Vm ) reaches the threshold for activation of the voltage-gated Na+ channels (VGNCs) Nav 1.2 and Nav 1.6. Yet, whereas it is known that these VGNCs differ in spatial distribution along the AIS and in biophysical properties, the understanding of the functional differences between the two channels remains elusive. Here, using ultrafast Na+ , Vm and Ca2+ imaging in combination with the partial block of Nav 1.2 by the peptide G1 G4 -huwentoxin-IV, we demonstrate an exclusive role of Nav 1.2 in shaping the generating AP. Precisely, we show that a selective block of ∼30% of Nav 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 Ca2+ -activated K+ channels (CAKCs). Indeed, Ca2+ influx via Nav 1.2 activates BK CAKCs determining the amplitude and the early phase of repolarisation of the AP in the AIS. By mean of control experiments using 4,9-Anhydrotetrodotoxin, which is a moderately selective inhibitor of Nav 1.6, we concluded that the Ca2+ influx shaping the early phase of the AP is exclusive of Nav 1.2. Hence, we mimicked this result with a NEURON model where the role of the different ion channels tested reproduced the experimental evidence. The exclusive role of Nav 1.2 reported here is important for understanding the physiology and pathology of neuronal excitability. KEY POINTS: We optically analysed the action potential that generates in the axon initial segment of mouse layer-5 neocortical pyramidal neurons and its associated Na+ and Ca2+ currents using ultrafast imaging techniques. We found that the partial selective block of the voltage-gated Na+ channel Nav1.2, produced by a recently developed peptide, widens the shape of the action potential in the distal part of the axon initial segment. We demonstrate that this effect is due to the reduction of the Ca2+ influx through Nav1.2 that activates BK Ca2+-activated K+ channels. To validate our conclusions, we generated a NEURON model that reproduces the ensemble of our experimental results. The present results indicate a specific role of Nav1.2 in the axon initial segment for the shaping of the action potential during its generation. Abstract figure legend In the axon initial segment of neocortical pyramidal neurons the voltage-gated Na+ channel Nav 1.2 contributes to the generation of the action potential by providing a Na+ current and a Ca2+ current that activates BK Ca2+ -activated K+ channels shaping the kinetics of the action potential. This article is protected by copyright. All rights reserved.

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