Kv3.3
Description: potassium voltage gated channel, Shaw-related subfamily, member 3 Gene: Kcnc3 Alias: Kv3.3, kcnc3, Kcr2-3, KShIIID
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
Rat Kv3.3 gene in CHO host cells datasheet |
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15 °Cshow 78 cells |
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25 °Cshow 172 cells |
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35 °Cshow 124 cells |
Gene
Transcript
| Species | NCBI accession | Length (nt) | |
|---|---|---|---|
| Human | NM_004977.3 | 6747 | |
| Mouse | NM_008422.3 | 5490 | |
| Rat | NM_053997.5 | 5268 |
Isoforms
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]
Kv3.3 predicted AlphaFold size
Methodology for AlphaFold size prediction and disclaimer are available here
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
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
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]
Biophysics
Model Kv3.3 (ID=28)
| Animal | Xenopus | |
| CellType | oocyte | |
| Age | 0 Days | |
| Temperature | 23.0°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)))) | |
Model Kv3.3 (ID=45)
| Animal | CHO | |
| CellType | CHO | |
| Age | 0 Days | |
| Temperature | 23.0°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)) | |
Kv3.3 Expression in CNS
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]
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]
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]
TEA
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
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Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna, Katherine Johnston
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