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Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons

Abstract

Neurons with the capacity to discharge at high rates—'fast-spiking' (FS) neurons—are critical participants in central motor and sensory circuits. It is widely accepted that K+ channels with Kv3.1 or Kv3.2 subunits underlie fast, delayed-rectifier (DR) currents that endow neurons with this FS ability. Expression of these subunits in heterologous systems, however, yields channels that open at more depolarized potentials than do native Kv3 family channels, suggesting that they differ. One possibility is that native channels incorporate a subunit that modifies gating. Molecular, electrophysiological and pharmacological studies reported here suggest that a splice variant of the Kv3.4 subunit coassembles with Kv3.1 subunits in rat brain FS neurons. Coassembly enhances the spike repolarizing efficiency of the channels, thereby reducing spike duration and enabling higher repetitive spike rates. These results suggest that manipulation of K3.4 subunit expression could be a useful means of controlling the dynamic range of FS neurons.

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Figure 1: In contrast to currents in FS neurons, Kv3.1b channel currents are inefficiently activated by spike waveforms.
Figure 2: FS neurons coexpress Kv3.1 and Kv3.4a mRNA and these subunits coassemble.
Figure 3: Kv3.4a channels activate at more negative membrane potentials than do Kv3.1b channels.
Figure 4: Kv3.4a + Kv3.1b heteromeric channels produce currents with properties resembling those seen in neurons.
Figure 5: Single-channel recordings show that coexpression of Kv3.1b and Kv3.4a subunits results in the formation of a channel with distinctive properties.
Figure 6: BDS-I produces a voltage-dependent block of currents in FS neurons and HEK293 cells.
Figure 7: The recovery of BDS-I sensitive current does not match that of Kv3 family channels.
Figure 8: BDS-I toxin broadens spikes and reduces spike frequency in FS neurons even in the presence of 2 mM Ca2+.

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Acknowledgements

This work was supported by the National Institute of Neurological Disorders and Stroke (NS26473, NS34696 to D.J.S. and a National Parkinson Foundation (NPF) grant to T.T.

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Correspondence to D. James Surmeier.

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Baranauskas, G., Tkatch, T., Nagata, K. et al. Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons. Nat Neurosci 6, 258–266 (2003). https://doi.org/10.1038/nn1019

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