研究发现，在小鼠皮层切片中L5椎体神经元，在Na_v1.2通道被部分抑制后，动作电位变宽。这是因为Na_v1.2具有一定的钙离子通透性。Na_v1.2被抑制30%后，在复极化时相的初期，通过Na_v1.2的钙内流减少，这样BK通道的激活减少，复极化速率减慢从而时程增加，最终导致动作电位变宽。动作电位的去极化时程由Na_v1.6所维持，故快速去极化时相不受影响。

Luiza Filipis, Laila Ananda Blömer, Jérôme Montnach, Gildas Loussouarn, Michel De Waard and Marco Canepari (2023) Na_v1.2 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

论文全文链接如下：

Na_v1.2 and BK channel interaction shapes the action potential in the axon initial segment - Filipis - 2023 - The Journal of Physiology - Wiley Online Library

Abstract

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) Nav1.2 and Nav1.6. 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+, Vm and Ca2+ imaging in combination with partial block of Nav1.2 by the peptide G1G4-huwentoxin-IV, we demonstrate an exclusive role of Nav1.2 in shaping the generating AP. Precisely, we show that selective block of ∼30% of Nav1.2 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 Nav1.2 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 Nav1.6, we concluded that the Ca2+ influx shaping the early phase of the AP is exclusive of Nav1.2. 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 Nav1.2 reported here is important for understanding the physiology and pathology of neuronal excitability.

图示摘要 GRAPHICAL ABSTRACT:

绿色：钠离子内流 (I_Na)

蓝色：钙离子内流 (I_Ca)

深黄色：钾离子外流 (I_K)

黄色背景中的黑色：完整动作电位。

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