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

Area of Science:

• Neuroscience
• Cellular Electrophysiology
• Ion Channel Physiology

Background:

• Action potentials (APs) in neocortical layer-5 pyramidal neurons originate in the axon initial segment (AIS).
• Voltage-gated sodium channels (VGNCs) Na_v 1.2 and Na_v 1.6 are crucial for AP generation but their distinct functional roles remain unclear.
• Understanding these roles is vital for comprehending neuronal excitability and related pathologies.

Purpose of the Study:

• To elucidate the specific functional contribution of Na_v 1.2 in shaping the AP at the AIS.
• To investigate the interplay between Na_v 1.2, Ca²⁺ influx, and BK channel activation during AP generation.
• To differentiate the roles of Na_v 1.2 and Na_v 1.6 in AP initiation.

Main Methods:

• Ultrafast imaging of Na⁺, V_m, and Ca²⁺ in mouse layer-5 neocortical pyramidal neurons.
• Selective partial blockade of Na_v 1.2 using G¹G⁴-huwentoxin-IV.
• Control experiments using 4,9-anhydrotetrodotoxin to inhibit Na_v 1.6.
• Computational neuron modeling to replicate experimental findings.

Main Results:

• Partial blockade of Na_v 1.2 significantly widened the AP in the distal AIS.
• This widening was attributed to reduced Ca²⁺ influx through Na_v 1.2, leading to decreased activation of BK Ca²⁺-activated K⁺ channels (CAKCs).
• Ca²⁺ influx via Na_v 1.2 was identified as the exclusive source for activating BK CAKCs, influencing AP amplitude and early repolarization.

Conclusions:

• Na_v 1.2 plays an exclusive role in shaping the AP during its generation in the AIS.
• The interaction between Na_v 1.2 and BK CAKCs is critical for determining AP characteristics in the AIS.
• These findings provide crucial insights into the specific functions of VGNC subtypes in neuronal excitability.