Abstract
Voltage-gated sodium channels are responsible for the initiation and propagation of action potentials (APs). Two brain isoforms, Nav1.1 and Nav1.6, have very distinct cellular and subcellular expression. Specifically, Nav1.1 is predominantly expressed in the soma and proximal axon initial segment of fast-spiking GABAergic neurons, while Nav1.6 is found at the distal axon initial segment and nodes of Ranvier of both fast-spiking GABAergic and excitatory neurons. Interestingly, an auxiliary voltage-gated sodium channel subunit, Navβ4, is also enriched in the axon initial segment of fast-spiking GABAergic neurons. The C-terminal tail of Navβ4 is thought to mediate resurgent sodium current, an atypical current that occurs immediately following the action potential and is predicted to enhance excitability. To better understand the contribution of Nav1.1, Nav1.6 and Navβ4 to high frequency firing, we compared the properties of these two channel isoforms in the presence and absence of a peptide corresponding to part of the C-terminal tail of Navβ4. We used whole-cell patch clamp recordings to examine the biophysical properties of these two channel isoforms in HEK293T cells and found several differences between human Nav1.1 and Nav1.6 currents. Nav1.1 channels exhibited slower closed-state inactivation but faster open-state inactivation than Nav1.6 channels. We also observed a greater propensity of Nav1.6 to generate resurgent currents, most likely due to its slower kinetics of open-state inactivation, compared to Nav1.1. These two isoforms also showed differential responses to slow and fast AP waveforms, which were altered by the Navβ4 peptide. Although the Navβ4 peptide substantially increased the rate of recovery from apparent inactivation, Navβ4 peptide did not protect either channel isoform from undergoing use-dependent reduction with 10 Hz step-pulse stimulation or trains of slow or fast AP waveforms. Overall, these two channels have distinct biophysical properties that may differentially contribute to regulating neuronal excitability.
Highlights
Voltage-gated sodium channels (VGSCs) mediate the inward current underlying the rising phase of the action potential and are key regulators of excitability
The axon initial segment is a key feature of neurons containing a high density of VGSCs and is the site of action potentials (APs) initiation [7,8,9]
We found that these channel isoforms have distinct biophysical properties that could contribute to different characteristics of VGSCs important for fast-firing
Summary
Voltage-gated sodium channels (VGSCs) mediate the inward current underlying the rising phase of the action potential and are key regulators of excitability. These channels are comprised of a principal α subunit encoded by nine genes that associate covalently and non-covalently with one or more auxiliary β subunits encoded by four genes [1]. The axon initial segment is a key feature of neurons containing a high density of VGSCs and is the site of AP initiation [7,8,9] These two channel isoforms are thought to have minimal overlap within the axon initial segment suggesting that they have distinct functions [4, 10]. It has previously been shown that different VGSC isoforms can play specific roles within the axon initial segment [11]
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