Kv3.4

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

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Introduction

Kv3.4, encoded by the gene KCNC4, is a voltage-gated potassium channel. Kv3.4 plays a key role in responding to chronic hypoxia, linked to Alzheimer's and Parkinson's diseases, influences resting potential in skeletal muscle, acts as a modulator in neuron channels, and plays a role in cell cycle progression in uterine smooth muscle cells.

Experimental data

Rat Kv3.4 gene in CHO host cells datasheet
Click for details 15 °C show 49 cells	Click for details 25 °C show 896 cells	Click for details 35 °C show 84 cells

Mouse Kv3.4 gene in CHO host cells
	Click for details 25 °C show 307 cells
Human Kv3.4 gene in CHO host cells
	Click for details 25 °C show 65 cells

Rat Kv3.4 gene in HEK host cells
	Click for details 25 °C show 194 cells
Rat Kv3.4 gene in CV1 host cells
	Click for details 25 °C show 141 cells

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Gene

Species	NCBI gene ID	Chromosome	Position
Human	3749	1	73766
Mouse	99738	3	22003
Rat	684516	2	35266

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_004978.6	4829
Mouse	NM_001356447.1	2953
Rat	NM_001415110.1	4318

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	Q03721	635
Mouse	Q8R1C0	628
Rat	Q63734	625

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NR_036437.2

4516

transcript variant 4

NM_004978.6

4829

NP_004969.2

635

transcript variant 1

isoform a

NM_001377330.1

4201

NP_001364259.1

624

transcript variant 5

isoform d

NM_001039574.3

4139

NP_001034663.1

626

transcript variant 3

isoform c

NM_001377331.1

3892

NP_001364260.1

403

transcript variant 6

isoform e

Predicted

XM_047419679.1

3615

XP_047275635.1

386

transcript variant X3

isoform X3

XM_006710625.5

3121

XP_006710688.1

618

transcript variant X1

isoform X1

XM_011541401.4

4441

XP_011539703.1

609

transcript variant X2

isoform X2

XM_047419680.1

3504

XP_047275636.1

306

transcript variant X5

isoform X5

XM_011541404.3

3202

XP_011539706.1

319

transcript variant X4

isoform X4

XM_024446790.2

3271

XP_024302558.1

661

transcript variant X6

isoform X6

XM_054336437.1

5291

XP_054192412.1

386

transcript variant X7

isoform X3

XM_054336435.1

3121

XP_054192410.1

618

transcript variant X1

isoform X1

XM_054336436.1

4447

XP_054192411.1

609

transcript variant X2

isoform X2

XM_054336439.1

3510

XP_054192414.1

306

transcript variant X5

isoform X5

XM_054336438.1

3202

XP_054192413.1

319

transcript variant X4

isoform X4

XM_054336440.1

3271

XP_054192415.1

661

transcript variant X6

isoform X6

Known

NM_001356447.1

2953

NP_001343376.1

630

transcript variant 1

isoform 1

NM_145922.3

3015

NP_666034.1

628

transcript variant 2

isoform 2

Predicted

XM_006502475.5

8422

XP_006502538.1

666

transcript variant X1

isoform X1

Known

NM_001122776.1

2858

NP_001116248.1

625

NM_001415110.1

4318

NP_001402039.1

627

isoform 1

Predicted

XM_039103131.1

9718

XP_038959059.1

608

transcript variant X3

isoform X3

XM_039103130.1

2944

XP_038959058.1

627

transcript variant X2

isoform X2

XM_039103129.1

5848

XP_038959057.1

663

transcript variant X1

isoform X1

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Post-Translational Modifications

PTM

Position

Type

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Glycosylation

256

N-linked (GlcNAc...) asparagine

Glycosylation

265

N-linked (GlcNAc...) asparagine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Glycosylation

260

N-linked (GlcNAc...) asparagine

Glycosylation

269

N-linked (GlcNAc...) asparagine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Modified residue

Phosphoserine

Glycosylation

257

N-linked (GlcNAc...) asparagine

Glycosylation

266

N-linked (GlcNAc...) asparagine

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Structure

Visual Representation of Kv3.4 Structure
Methodology for visual representation of structure available here

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

Kv3.4 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	6181.43	source
Mouse	5557.04	source
Rat	3632.30	source

Methodology for AlphaFold size prediction and disclaimer are available here

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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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Biophysics

Compare wit figure 1 in [302].

Model Kv3.4 (ID=29)

Animal	Xenopus
CellType	oocyte
Age	0 Days
Temperature	23.0°C
Reversal	-65.0 mV
Ion	K +
Ligand ion
Reference	[281] 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))))

MOD - xml - channelML

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Expression and Distribution

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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CNS Sub-cellular 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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Function

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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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]