Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing

doi:10.1016/S0166-2236(00)01892-0

Trends in Neurosciences

Volume 24, Issue 9, 1 September 2001, Pages 517-526

https://doi.org/10.1016/S0166-2236(00)01892-0 Get rights and content

Abstract

Analysis of the Kv3 subfamily of K⁺ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K⁺ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height. The short spike duration and the rapid deactivation of the Kv3 currents after spike repolarization maximize the quick recovery of resting conditions after an action potential. Several neurons in the mammalian CNS have incorporated into their repertoire of voltage-dependent conductances a relatively large number of Kv3 channels to enable repetitive firing at high frequencies – an ability that crucially depends on the special properties of Kv3 channels and their impact on excitability.

Section snippets

Molecular characteristics of Kv3 subfamily members

Both rodents and humans possess four Kv3 genes: Kv3.1, Kv3.2, Kv3.3 and Kv3.4 (6, 7). All four Kv3 genes generate multiple protein isoforms by alternative splicing, which produces versions with different intracellular C-terminal sequences. There are now 13 different Kv3 proteins known in mammals (Kv3.1a–Kv3.1b, Kv3.2a–Kv3.2d, Kv3.3a–Kv3.3d and Kv3.4a–Kv3.4c), yet the currents expressed in heterologous expression systems by the spliced isoforms of each Kv3 gene are virtually indistinguishable.

Kv3 proteins express voltage-gated channels with unusual properties in heterologous expression systems and in native cells

Chinese hamster ovary (CHO) cells transfected with cDNAs of transcripts from each of the four Kv3 genes (Kv3.1b, Kv3.2a, Kv3.3d and Kv3.4a) have large voltage-dependent K⁺ currents with similar voltage dependencies (Fig. 1a,b) 6, 7. The currents become apparent when the membrane is depolarized to potentials more positive than approximately −20 mV, which is more depolarized than any other known mammalian voltage-gated K⁺ channel by at least 10–20 mV (Ref. 16). Another crucial property of the

Kv3 currents are activated specifically during action potential repolarization

The electrophysiological properties of Kv3 channels suggest a specific role in action potential repolarization 6, 7, 11, 15, 18, 33, 34, 35, 36, 37, 38. Given their voltage dependence, it is unlikely that Kv3 channels will be significantly activated other than during action potentials, and only once these have reached their peak. Confirmation of this hypothesis has come from recording currents from HEK293 cells transfected with Kv3.1 or Kv3.2 cDNAs voltage clamped to a waveform in the shape of

Kv3 channels are prominently expressed in neurons that fire at high frequency

In rodents, three of the four known Kv3 genes (Kv3.1–Kv3.3) are prominently expressed in the CNS. Kv3.4 transcripts are abundant in skeletal muscle and sympathetic neurons, but are only weakly expressed in a few neuronal types in the brain, often in neurons that also express other Kv3 genes 6, 15, 19, 44, 45. However, as a single Kv3.4 subunit is capable of enabling fast inactivating properties to a Kv3 tetrameric channel ¹⁵ (Fig. 1c), they might be important functional determinants, even when

Kv3 channels are necessary for high-frequency repetitive firing

How do the unique electrophysiological properties of Kv3 channels lend themselves to facilitating high frequency repetitive firing? As discussed, neurons can use large numbers of Kv3 channels to accelerate action potential repolarization with a minimum risk of compromising action potential generation (Box 1). By increasing the rate of spike repolarization and thus keeping action potentials short, Kv3 currents can reduce the amount of Na⁺ channel inactivation occurring during the action

Modulation of Kv3 K⁺ channels

In numerous systems, modulation of voltage-gated channels by kinases and phosphatases provides additional mechanisms to dynamically regulate membrane properties 60, 61, 62, 63. Channels formed by Kv3 subfamily members are targets for such modulation 11, 37, 49, 64, 65, 69. Given the dominant functional role of Kv3 channels in some neurons, their phosphorylated state could have profound influences on the physiological properties of the cell and the network to which it is connected (Fig. 5).

Kv3.2

Concluding remarks

Together, the experimental data and computer modeling support the idea that the activation range and fast deactivation kinetics of Kv3 channels function specifically to enable neurons to fire repetitively at high frequencies 5, 6, 23, 24, 40, 43, 49, 69. Kv3 channels might have been a common solution in vertebrates to the problems imposed by high-frequency repetitive firing, as they appear to be present in most neurons that can fire repetitively at high frequencies. It remains to be seen

Acknowledgements

We thank our colleagues E. Phillips-Tansey, J. Du, M. Atzori, L. Zhang, C. Leonard, A. Erisir, D. Contreras, C. Kentros, H. Moreno, E. Vega, Y. Amarillo, M. Nadal, M. Saganich, A. Ozaita, A. Chow, P. Rhodes and D. Lau for their contributions to this work. We also thank J. Rae for Kv3.3d cDNA. Our research is supported by NIH Grants NS30989 and NS35215, and NSF grant IBN 0078297 to B.R.

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Trends in Neurosciences

ReviewKv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing

Abstract

Section snippets

Molecular characteristics of Kv3 subfamily members

Kv3 proteins express voltage-gated channels with unusual properties in heterologous expression systems and in native cells

Kv3 currents are activated specifically during action potential repolarization

Kv3 channels are prominently expressed in neurons that fire at high frequency

Kv3 channels are necessary for high-frequency repetitive firing

Modulation of Kv3 K+ channels

Concluding remarks

Acknowledgements

J. Membr. Biol.

J. Neurophysiol.

J. Neurosci.

J. Neurobiol.

J. Neurophysiol.

Science

Curr. Opin. Neurobiol.

Interneurons unbound

Nat. Rev. Neurosci.

Interneurons in the hippocampus

Hippocampus

Fast Oscillations in Cortical Circuits

Two voltage-dependent K+ conductances with complimentary functions in postsynaptic integration at a central auditory synapse

J. Neurosci.

Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory nucleus

J. Physiol.

Contributions of the Kv3 channels to neuronal excitability

Ann. New York Acad. Sci.

Shaw-related K+ channels in mammals

Role of alternatively-spliced C-termini in the subcellular localization of Kv3 potassium channels in neurons

Soc. Neurosci. Abstr.

Elimination of rapid potassium channel inactivation by phosphorylation of the inactivation gate

Neuron

Modulation of Kv3.3 K+ channels by oxidation and phosphorylation

Soc. Neurosci. Abstr.

Phosphorylation may be required to activate Shaw related K+ channels

Soc. Neurosci. Abstr.

Differential expression of Shaw-related K+ channels in the rat central nervous system

J. Neurosci.

Molecular diversity of K+ channels

Ann. New York Acad. Sci.

Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines

Mol. Pharmacol.

Developmental expression and functional characterization of the potassium-channel subunit Kv3.1b in parvalbumin-containing interneurons of the rat hippocampus

J. Neurosci.

Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier K+ current in projecting neurons from the globus pallidus

J. Neurophysiol.

Kv3.3 potassium channels in lens epithelium and corneal endothelium

Exp. Eye Res.

Role of transmembrane segment S5 on gating of voltage-dependent K+ channels

J. Gen. Physiol.

Determinants of voltage-dependent gating and open-state stability in the S5 segment of Shaker potassium channels

J. Gen. Physiol.

Function of specific K+ channels in sustained high-frequency firing of fast-spiking neocortical interneurons

J. Neurophysiol.

A Kv3-like persistent, outwardly rectifying, Cs+-permeable, K+ current in rat subthalamic nucleus neurones

J. Physiol.

The contribution of dendritic Kv3 K+ channels to burst threshold in a sensory neuron

J. Neurosci.

Electrophysiological characterization of voltage-gated K+ currents in cerebellar basket and Purkinje cells: Kv1 and Kv3 channel subfamilies are present in basket cell nerve terminals

J. Neurosci.

Delayed rectifier currents in rat globus pallidus neurons are attributable to Kv2.1 and Kv3.1/3.2 K+ channels

J. Neurosci.

Shaker K+ channel subunits from heteromultimeric channels with novel functional properties

Biochem. Biophys. Res. Commun.

Microheterogeneity in heteromultimeric assemblies formed by Shaker (Kv1) and Shaw (Kv3) subfamilies of voltage-gated K+ channels

Proc. R. Soc. London B Biol. Sci.

K+ channel expression distinguishes subpopulations of parvalbumin and somatostatin-containing neocortical interneurons

J. Neurosci.

Review
Kv3 channels: voltage-gated K⁺ channels designed for high-frequency repetitive firing

Modulation of Kv3 K⁺ channels

Two voltage-dependent K⁺ conductances with complimentary functions in postsynaptic integration at a central auditory synapse

Shaw-related K⁺ channels in mammals

Modulation of Kv3.3 K⁺ channels by oxidation and phosphorylation

Phosphorylation may be required to activate Shaw related K⁺ channels

Differential expression of Shaw-related K⁺ channels in the rat central nervous system

Molecular diversity of K⁺ channels

Pharmacological characterization of five cloned voltage-gated K⁺ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines

Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier K⁺ current in projecting neurons from the globus pallidus

Role of transmembrane segment S5 on gating of voltage-dependent K⁺ channels

Function of specific K⁺ channels in sustained high-frequency firing of fast-spiking neocortical interneurons

A Kv3-like persistent, outwardly rectifying, Cs+-permeable, K⁺ current in rat subthalamic nucleus neurones

The contribution of dendritic Kv3 K⁺ channels to burst threshold in a sensory neuron

Electrophysiological characterization of voltage-gated K⁺ currents in cerebellar basket and Purkinje cells: Kv1 and Kv3 channel subfamilies are present in basket cell nerve terminals

Delayed rectifier currents in rat globus pallidus neurons are attributable to Kv2.1 and Kv3.1/3.2 K⁺ channels

Shaker K⁺ channel subunits from heteromultimeric channels with novel functional properties

Microheterogeneity in heteromultimeric assemblies formed by Shaker (Kv1) and Shaw (Kv3) subfamilies of voltage-gated K⁺ channels

K⁺ channel expression distinguishes subpopulations of parvalbumin and somatostatin-containing neocortical interneurons