Human Nav1.6 channels generate larger resurgent currents than human Nav1.1 channels, but the Navβ4 peptide does not protect either isoform from use-dependent reduction

Reesha R. Patel, Cindy Barbosa, Yucheng Xiao, Theodore Cummins

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 wholecell 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.

Original languageEnglish
Article numbere0133485
JournalPLoS One
Volume10
Issue number7
DOIs
StatePublished - Jul 16 2015

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action potentials
inactivation
Protein Isoforms
GABAergic Neurons
Action Potentials
axons
peptides
Peptides
sodium channels
neurons
Voltage-Gated Sodium Channels
Neurons
tail
Tail
Ranvier's Nodes
Clamping devices
Carisoprodol
sodium
Brain
brain

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Human Nav1.6 channels generate larger resurgent currents than human Nav1.1 channels, but the Navβ4 peptide does not protect either isoform from use-dependent reduction. / Patel, Reesha R.; Barbosa, Cindy; Xiao, Yucheng; Cummins, Theodore.

In: PLoS One, Vol. 10, No. 7, e0133485, 16.07.2015.

Research output: Contribution to journalArticle

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