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Kv3.3

potassium voltage gated channel, Shaw-related subfamily, member 3
Synonyms: Kv3.3 kcnc3 Kcr2-3 KShIIID. Symbol: Kcnc3

Introductions


Kv3 family voltage-dependent potassium channels have fast activation and deactivation kinetics with high activation thresholds, allowing neurons that express these channels to fire trains of action potentials at high frequencies [302]. In situ hybridization and immunohistochemistry have shown that Kv3.3 subunits are highly expressed in the cerebellar cortex, in particular, in granule cells. It is also prominently expressed throughout other areas of the CNS (central nervous system), particularly in Purkinje cells [1665]

Genes


Kcnc3 : potassium voltage gated channel, Shaw-related subfamily, member 3

RGD ID Chromosome Position Species
621358 1 95066641-95080847 Rat
733064 7 51846256-51860121 Mouse
733063 19 50818765-50832634 Human

Transcripts


Acc No Sequence Length Source
NM_053997 NCBI
NM_008422 NCBI
NM_004977 NCBI

Ontologies


Accession Name Definition Evidence
GO:0016020 membrane Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. IEA
GO:0016021 integral to membrane Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane. IEA
GO:0008076 voltage-gated potassium channel complex A protein complex that forms a transmembrane channel through which potassium ions may cross a cell membrane in response to changes in membrane potential. IEA

Interactions


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]

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]

Proteins


Resemblance of Kv3 family

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 [302]

Structures


Kv3.1 [1665]

The Kv3 subfamily, consisting of four genes (encoding Kv3.1, Kv3.2, Kv3.3 and Kv3.4), have some distinct functional properties. They activate at high thresholds (−10 mV) and activate and deactivate more rapidly than other Kv channels; these properties enable neurons to fire at high frequencies [2]. The predicted membrane topology of a Kv3 subunit shows six transmembrane domains (S1–S6), a voltage sensor in S4, and a pore loop between S5 and S6

Distributions


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

Kv1.3 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]

Expressions


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]

Functionals


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]

Kinetics


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]

Models


[1] Kv3.3 (Model ID = 28)

AnimalXenopus 111
CellType oocyte
Age 0 Days
Temperature23.0°C
Reversal -65.0 mV
Ion K +
Ligand ion
Reference A J Rashid et. al; J. Neurosci. 2001 Jan 1
mpower 1.0
mInf 1/(1+exp(((v -(18.700))/(-9.700))))
mTau 20.000/(1+exp(((v -(-46.560))/(-44.140))))

MOD xml channelML

[2] Kv3.3 (Model ID = 45)

AnimalCHO 175
CellType CHO
Age 0 Days
Temperature23.0°C
Reversal 82.0 mV
Ion K +
Ligand ion
Reference Rooma Desai et. al; J. Biol. Chem. 2008 Aug 8
mpower 2.0
mInf 1/(1+exp((v-35)/-7.3))
mTau 0.676808 +( 27.913114 / (1 + exp((v - 22.414149)/9.704638)))
hpower 1.0
hInf 0.25+( 0.75 /(1+exp((v-(-28.293856))/29.385636)))
hTau 199.786728 + (2776.119438 * exp(-v/7.309565))

MOD xml channelML

References


[20 : 18539595]
[280 : 11150328]
[315 : 16923152]
[316 : 16553620]
[318 : 17444489]
[485 : 12098017]
[486 : 11494252]
[487 : 12144039]
[489 : 9037088]
[1637 : 22289912]
[1638 : 24312005]
[1639 : 20857303]
[1640 : 20471378]
[1641 : 12923191]
[1663 : 19387585]
[1664 : 20712895]
[1665 : 23734863]
[1666 : 20357073]
[1667 : 16354911]
[1668 : 10712820]
[302 : 11506885]
[488 : 11517255]
[1831 : 15547932]

Credits


Editor : Admin.

Contributors : Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite : [Editor], [Contributors]. Accessed on [Date] Channelpedia , http://channelpedia.epfl.ch/ionchannels/13