Channelpedia

Kv3.3

Description: potassium voltage gated channel, Shaw-related subfamily, member 3
Gene: Kcnc3
Alias: Kv3.3, kcnc3, Kcr2-3, KShIIID

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Introduction

Kv3.3, encoded by the gene KCNC3, is a voltage-gated potassium channel. Kv3.3 plays a key role in high-frequency firing and motor coordination Mutations in Kv3.3 lead to disruptions in sound localization and contributing to alcohol hypersensitivity and spontaneous myoclonus.


Experimental data

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Gene

Species NCBI gene ID Chromosome Position
Human 3748 19 21599
Mouse 16504 7 17770
Rat 117101 1 14205

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Transcript

Species NCBI accession Length (nt)
Human NM_004977.3 6747
Mouse NM_008422.3 5490
Rat NM_053997.5 5268

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Protein Isoforms

Species Uniprot ID Length (aa)
Human Q14003 757
Mouse Q63959 769
Rat Q01956 889

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform

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Post-Translational Modifications

Protein Kinase C (PKC)

Kv3.3 currents are potently enhanced by activation of PKC. Two N-terminal serine residues are consensus sites for PKC phosphorylation and are required for enhancement of Kv3.3 currents. PKC modulation of Kv3.3 channels could play a role in dynamic adaptation of auditory brainstem circuits. [20]

PTM
Position
Type

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Structure

Kv3.3 predicted AlphaFold size

Species Area (Å2) Reference
Human 6214.21 source
Mouse 6149.91 source
Rat 8330.73 source

Methodology for AlphaFold size prediction and disclaimer are available here


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Kinetics

Kv3.3
Visual Representation of Kv3.3 Structure
Methodology for visual representation of structure available here

Both Kv3.3b and Kv3.4 express as a transient or A-type current, but inactivation of Kv3.4 channels (τ = 15.9 ms) is much faster than Kv3.3 (τ = 200 ms) [1638]

SINGLE CHANNEL CONDUCTANCE

Kv3.1 Kv3.1

The single channel slope conductance measured under presumed equimolar K+ in the on-cell configuration ranged between 32 and 38 pS and was not significantly different for channels expressed in CHO or HEK cells. Single channel recordings were recorded in the on-cell or outside-out configuration and were acquired at 2–5 kHz and digitally filtered during analysis at 1–2 kHz. [1641]



Kv3.3 Channel Kinetics in CHO and HEK cells

Kv3.1 Kv3.1

Deactivation was rapid in both CHO and HEK cells (CHO τ = 0.55 to 1.09 ms; HEK τ = 0.41 to 0.81 ms) and voltage-dependent between –80 and –30 mV. As found for activation, the τ of deactivation in CHO cells was significantly slower than that in HEK cells [1641] Kv3.3 and Kv3.4 currents are of the A-type, although Kv3.3 currents inactivate slowly whereas Kv3.4 currents inactivate relatively quickly [302]


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Biophysics


Model Kv3.3 (ID=28)      

AnimalXenopus
CellType oocyte
Age 0 Days
Temperature23.0°C
Reversal -65.0 mV
Ion K +
Ligand ion
Reference [280] A J Rashid et. al; J. Neurosci. 2001 Jan 1
mpower 1.0
m Inf 1/(1+exp(((v -(18.700))/(-9.700))))
m Tau 20.000/(1+exp(((v -(-46.560))/(-44.140))))

MOD - xml - channelML


Model Kv3.3 (ID=45)      

AnimalCHO
CellType CHO
Age 0 Days
Temperature23.0°C
Reversal 82.0 mV
Ion K +
Ligand ion
Reference [20] Leonard K Kaczmarek et. al; J. Biol. Chem. 2008 Aug 8
mpower 2.0
m Inf 1/(1+exp((v-35)/-7.3))
m Tau 0.676808 +( 27.913114 / (1 + exp((v - 22.414149)/9.704638)))
hpower 1.0
h Inf 0.25+( 0.75 /(1+exp((v-(-28.293856))/29.385636)))
h Tau 199.786728 + (2776.119438 * exp(-v/7.309565))

MOD - xml - channelML


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Expression and Distribution

Kv3.3 Expression in CNS

Kv3.1 [318]

Kv3.3 is widely expressed in the nervous system, including cerebellum, basal ganglia and spinal cord [487], areas implicated in the precise execution of motor tasks. Kv3.3 is the dominant Kv3 family member in the auditory brainstem, for example in the calyces of Held, the large presynaptic terminals that provide input to the MNTB, and also in the superior olivary complex, where the axons of MNTB neurons end.[486]

In Purkinje cells, Kv3.3 is expressed in the absence of Kv3.1. [318]

Kv3.1 and Kv3.3 mRNA transcripts overlap in many areas, particularly in the posterior part of the brain and in the spinal cord. Kv3.3 are expressed in many neuronal populations, including most auditory central processing neurons (some of which also express Kv3.2) and many cranial nerve nuclei [302]


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CNS Sub-cellular Distribution

In the apteronotid electrosensory lateral line lobe, a homolog of the Kv3.3 K+ channel subtype is distributed over the entire soma–dendritic axis of pyramidal cells. [280]

Kv3.3 is distributed an axonal membranes and synaptic terminals where they influence spike repolarization [1639]

Mammalian Kv3.3 potassium channel, AptKv3.3, is expressed at high levels in both the somas and dendrites of ELL pyramidal cells. In addition, preliminary in situ hybridization studies indicated that a second Kv3 subtype, AptKv3.1, was also expressed in these neurons [1667]

Kv3.3-immunoreactivity was widespread in the vestibular nuclei and was detected in somata, dendrites and synaptic terminals

Kv3.3 in Dendrites

Voltage-gated potassium channel subunit Kv3.3 is expressed in the distal dendrites of Purkinje cells. However, the functional relevance of this dendritic distribution is not understood. To study the physiological relevance of altered dendritic excitability, we measured Ca(2+) changes throughout the dendritic tree in response to climbing fiber activation. Ca(2+) signals were specifically enhanced in distal dendrites of Kv3.3 knockout Purkinje cells, suggesting a role for dendritic Kv3.3 channels in regulating propagation of electrical activity and Ca(2+) influx in distal dendrites [1666]


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Function

NEURONAL FUNCTION

Due to their biophysical properties, Kv3 channels facilitate firing of narrow action potentials at high frequency, and their interaction with resurgent Na+ currents support spontaneous action potential firing in the absence of synaptic inputs. In a previous electrophysiological study, it was shown that neurons of deep cerebellar nuclei (DCN) lacking glutamic acid decarboxylase (GAD-), the GABA-synthesizing enzyme, fire at higher rates and exhibit faster action potentials than GAD+ DCN neurons. These observations correlated with a distinct distribution of Kv3.1b and Kv3.3 potassium channel subunits in GAD- and GAD+ dentate neurons [1639]

The functional properties of zebrafish Kv3.3 channels are consistent with a role in facilitating fast, repetitive firing of action potentials in neurons. The functional effects of SCA13 mutations are well conserved between human and zebrafish Kv3.3 channels [1664]

KO MICE BEHAVIOUR

Mice lacking both Kv3.1 and Kv3.3 subunits display severe motor disturbances, such as ataxia, tremor, myoc- lonus as well as high alcohol hypersensitivity, while there is only a modest motor dysfunction in mice lacking only one of the subunits (Kv3.1 or Kv3.3). Indeed, the number of intact Kv3.1/3.3 alleles correlates with the severity of ataxia, indicating some degree of functional redundancy at least in granule cell parallel fibers [1639]

In the apteronotid electrosensory lateral line lobe, a Kv3.3 K+ channel subtype acts to repolarize Na+ spike discharge in both the soma and proximal apical dendrites. [280]

Mice lacking either Kv3.1 or Kv3.3 subunits display relatively moderate electrophysiological and behavioral changes [489]. Knocking out both, Kv3.1 and Kv3.3, however, ensues dramatic physiological and behavioral alterations that include hyperactivity, sleep loss, myoclonus, tremor, alcohol hypersensitivity and severe ataxia [488].

Sound Localization

Mutation in the Kv3.3 Voltage-Gated Potassium Channel Causing Spinocerebellar Ataxia 13 Disrupts Sound-Localization Mechanisms

Spinocerebellar Ataxia

Mutations in Kv3.3 cause the neurological disorder SCA13 (spinocerebellar ataxia type 13) [1665]

Alcohol Hypersensitivity

Alcohol hypersensitivity, increased locomotion, and spontaneous myoclonus in mice lacking the potassium channels Kv3.1 and Kv3.3 [488]


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Interaction

TEA

Kv3.1 [1666]

In both cell types, substantial block was obtained for whole-cell currents in the range of 200 μM TEA or less. There was a significantly lower IC50 for whole-cell currents expressed in CHO compared with HEK cells (CHO IC50 = 67.5 ± 4.2 μM, HEK IC50 = 152 ± 27 μM). The IC50 value for TEA obtained in HEK cells was equivalent to that reported for Kv3.3a expressed in oocytes at 140 ± 43 μM. AptKv3.3 currents expressed in HEK cells were also highly sensitive to externally applied 4-AP (IC50 < 100 μM) [1641]

Mutations

Zebrafish Kv3.3 activates over a depolarized voltage range and deactivates rapidly. An amino-terminal extension mediates fast, N-type inactivation. The kcnc3a gene is alternatively spliced, generating variant carboxyl-terminal sequences. The R335H mutation in the S4 transmembrane segment, analogous to the SCA13 mutation R420H, eliminates functional expression. When co-expressed with wild type, R335H subunits suppress Kv3.3 activity by a dominant negative mechanism. The F363L mutation in the S5 transmembrane segment, analogous to the SCA13 mutation F448L, alters channel gating. F363L shifts the voltage range for activation in the hyperpolarized direction and dramatically slows deactivation [1664]


References

20

Desai R et al. Protein kinase C modulates inactivation of Kv3.3 channels.
J. Biol. Chem., 2008 Aug 8 , 283 (22283-94).

280

Rashid AJ et al. The contribution of dendritic Kv3 K+ channels to burst threshold in a sensory neuron.
J. Neurosci., 2001 Jan 1 , 21 (125-35).

302

Rudy B et al. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing.
Trends Neurosci., 2001 Sep , 24 (517-26).

315

Joho RH et al. Behavioral motor dysfunction in Kv3-type potassium channel-deficient mice.
Genes Brain Behav., 2006 Aug , 5 (472-82).

318

485

486

Minassian NA et al. Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13.
J. Physiol. (Lond.), 2012 Apr 1 , 590 (1599-614).

Veys K et al. Kv3.3b expression defines the shape of the complex spike in the Purkinje cell.
Front Cell Neurosci, 2013 , 7 (205).

Fernandez FR et al. Inactivation of Kv3.3 potassium channels in heterologous expression systems.
J. Biol. Chem., 2003 Oct 17 , 278 (40890-8).

Sung MJ et al. Effect of psoralen on the cloned Kv3.1 currents.
Arch. Pharm. Res., 2009 Mar , 32 (407-12).

Deng Q et al. A C-terminal domain directs Kv3.3 channels to dendrites.
J. Neurosci., 2005 Dec 14 , 25 (11531-41).

Rae JL et al. Kv3.3 potassium channels in lens epithelium and corneal endothelium.
Exp. Eye Res., 2000 Mar , 70 (339-48).


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Credits

Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna, Katherine Johnston

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/13/ , accessed on 2024 Dec 02