Kv3.4

Description: potassium voltage gated channel, Shaw-related subfamily, member 4
Gene: Kcnc4 Synonyms: Kv3.4, kcnc4, Kcr2-4, KSHIIIC

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Introduction

The Kv3 pharmacological and biophysical fingerprint (remarkably fast activation and deactivation, high threshold [302]) mirrors certain neuronal K+ currents [490], and, in many CNS neurons, a “fast spiking” phenotype is conferred by Kv3 channels [491].

Both rodents and humans possess four Kv3 genes: Kv3.1, Kv3.2, Kv3.3 and Kv3.4. 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. [302]

Experimental data

Rat Kv3.4 gene in CHO host cell datasheet
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Mouse Kv3.4 gene in CHO host cell
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Human Kv3.4 gene in CHO host cell
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Rat Kv3.4 gene in HEK host cell
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Rat Kv3.4 gene in CV1 host cell
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Gene

RGD ID	Chromosome	Position	Species
1589169		-	Rat
1616662	3	107241221-107261816	Mouse
1348258	1	110753336-110776674	Human

Kcnc4 : potassium voltage gated channel, Shaw-related subfamily, member 4

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Transcript

Acc No	Sequence	Length	Source
NM_001122776	n/A	n/A	NCBI
NM_145922	n/A	n/A	NCBI
NM_004978	n/A	n/A	NCBI
NM_001039574	n/A	n/A	NCBI

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Ontology

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Interaction

BDS-I and BDS-II

Sea anemone toxins BDS-I and BDS-II (“blood depressing substance”) are highly specific blockers for Kv3.4 subunits in expression systems.[495]

BDS is not subunit selective but also inhibits Kv3.1 and Kv3.2 subunits.[23]

PMA

Phorbol 12-myristate 13-acetate (20nM)reduced inactivation of the current [1642]

OAG

1-oleoyl-2-acetyl-rac-glycerol (60uM) also reduced inactivation of the current in a time dependent manner [1642]

Serine 82 of MiRP2

Phosphorylation of serine 82 of MiRP2 (MiRP2-S82P) is required for MiRP2 to produce the normal shift in voltagedependent activation of Kv3.4 observed in vivo. [21]

1,4-diazabicyclo[2.2.2]octane (DABCO)

The bicyclic molecule 1,4-diazabicyclo[2.2.2]octane (DABCO) does not inhibit Kv2.1 or Kv3.4 (1 mM), but submillimolar concentrations of various cell-safe substituted mono- and di-DABCO forms inhibit both channels whereas Kv4.2 channels are relatively insensitive. [22]

Kv3.1

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 [1633]

Cav1.2

Kv3.4 and Cav1.2, two high-voltage-activated ion channels, may act together to control Ca²⁺ dependent electrical activity of pioneer axons and play important roles during axon pathfinding [1646]

Alcohol

a hydrophobic point mutation within a cytoplasmic loop of an ethanol-insensitive K+ channel (human Kv3.4) was sufficient to allow significant inhibition by n-alkanols, with a dose-inhibition relation that closely resembled that of wildtype Shaw2 channels [1749]

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Protein

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Structure

KV3.4

Structure of inactivation gates derived from the mammalian Kv channel 3.4. Backbone (left) and surface structure (right). Backbone representation shows 8th lowest-energy structures for each peptide. N and C, NH2 and COOH terminals, respectively. Kv3.4 peptide showed compact folding through- out the molecule but did not exhibit any typical secondary structure

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Distribution

Ultrastructural analysis also revealed Kv3.4-IR postsynaptically in somata and dendrites, where it was often clustered at postsynaptic densities.

The boxed areas in A are shown at higher magnification in B–D. Kv3.4-IR is present in both the presynaptic terminals and in the postsynaptic dendrite, where it appeared to be located close to the active zone, indicating a possible relationship with the PSD [1643]

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Expression

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. [290]

Kv3.4 channel subunits can be found throughout the thoracic spinal cord and brainstem, including regions involved in autonomic control.

Expression in Rat Brain

Transcripts of three of these genes,KV3.1, KV3.3, and KV3.4, exhibit localizations more similar to eachother than thoseof KV3.2 transcripts. At thesametime, many regions that express KV3.1, KV3.3, or KV3.4 mRNAs prominently, such as the cerebellar cortex, the spinalcord, the reticular thalamic nucleus, the inferior colliculus, and many nuclei in the brainstem, appear to express little or no KV3.2 transcripts [1644]

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Functional

Kv3.4 subunits have been implicated recently in responses to chronic hypoxia [492] and, significantly, in the etiology of Alzheimer’s [493] and Parkinson’s diseases [494].

Kv3.4 subunits associate with MiRP2 proteins in skeletal muscle to form subthreshold-operating channels that contribute to setting the resting potential of muscle cells. [497]

Neuronal Function

Kv3.4 is expressed in neurons also expressing KV3.1 or KV3.3 mRNAs, KV3.4 subunits may act in CNS neurons as modulators of the inactivation properties of channels composed mainly of KV3.1 and KV3.3 proteins. The electrophysiological studies described in this article indicate that small amounts of KV3.4 transcripts might be sufficient to impart fast inactivating properties to channels composed mainly of the other ShIII sub- units. Similar studies with ShI subunits have also shown that the presence of a single inactivating subunit is sufficient to impart inactivating properties in the resultant channels [1644]

Uterine Artery Smooth Muscle Cells

Kv3.4 channels exert a permissive role in the cell cycle progression of proliferating uterine VSMCs, as their blockade induces cell cycle arrest after G2/M phase completion. The modulation of resting membrane potential (V(M)) by Kv3.4 channels in proliferating VSMCs suggests that their role in cell cycle progression could be at least in part mediated by their contribution to the hyperpolarizing signal needed to progress through the G1 phase [1750]

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Kinetics

A crucial property of the currents mediated by Kv3.1 and Kv3.2 channels (as well as Kv3.3 and Kv3.4 channels before they fully inactivate) is their fast rate of deactivation upon repolarization (e.g. at −70 mV, Kv3.1b currents deactivate with a time constant of ≤1 ms at room temperature), which is significantly faster than that of any other known neuronal voltage-gated K+ channels by about an order of magnitude. [496]

Kv3.4 Kinetics

In Xenopus laevis oocytes, hKv3.4 expresses avoltage- dependent outward K+current which, in response to a step depolarization, inactivates rapidly and almost completely within approximately 100 ms. Whole-oocyte outward K+ currents were elicited by 112 ms step depolarizations between -50 and +50 mV in 10 mV increments from a holding potential of -100 mV [1642]

Single Channel Currents

Single Channel records show that all 33 of the Sh channels containing a toe 4 carboxyl domain show a similar single channel conductance. This emphasizes on the consistent properties of the Sh channel family [1645]

Rat Kv3.4 Kinetics Expressed in CHO Cells

While Kv3.4 channels passed only outward currents when expressed in CHO cells and studied in large cell-attached patches with roughly equal potassium levels on either side of the membrane, MiRP2-Kv3.4 channels passed both inward and outward currents. This can be understood from the normalized conductance-voltage relationships for the two channel types [497]

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Model

Compare wit figure 1 in [302].

Model Kv3.4 (ID=29) Edit

Animal	Xenopus
CellType	oocyte
Age	0 Days
Temperature	23.0°C
Reversal	-65.0 mV
Ion	K +
Ligand ion
Reference	H Moreno et. al; Proc. Biol. Sci. 1992 Apr 22
mpower	1.0
m Inf	1/(1+exp(((v -(-3.400))/(-8.400))))
m Tau	10.000/(1+exp(((v -(4.440))/(38.140))))
hpower	1.0
h Inf	1/(1+exp(((v -(-53.320))/(7.400))))
h Tau	20000.000/(1+exp(((v -(-46.560))/(-44.140))))