Kv1.4

Description: potassium voltage-gated channel, shaker-related subfamily, member 4
Gene: Kcna4
Alias: Kv1.4, kcna4, kv4, RK3, RHK1, KCHAN

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Introduction

Kv1.4, encoded by the gene KCNA4, is a member of the potassium voltage-gated channel subfamily A. Kv1.2 is widely distributed in teh central nervous system. Derugaltion of Kv1.4 leads to hypertrophy and heart failure

Experimental data

Rat Kv1.4 gene in CHO host cells datasheet
Click for details 15 °C show 99 cells	Click for details 25 °C show 163 cells	Click for details 35 °C show 88 cells

Mouse Kv1.4 gene in CHO host cells datasheet
	Click for details 25 °C show 83 cells	Click for details 35 °C show 54 cells
Human Kv1.4 gene in CHO host cells datasheet
	Click for details 25 °C show 63 cells	Click for details 35 °C show 61 cells

Rat Kv1.4 gene in HEK host cells datasheet
	Click for details 25 °C show 91 cells	Click for details 35 °C show 59 cells
Rat Kv1.4 gene in CV1 host cells datasheet
	Click for details 25 °C show 60 cells	Click for details 35 °C show 85 cells

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Gene

Species	NCBI gene ID	Chromosome	Position
Human	3739	11	7300
Mouse	16492	2	36215
Rat	25469	3	21605

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_002233.4	4190
Mouse	NM_021275.4	4844
Rat	NM_012971.3	3127

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	P22459	653
Mouse	Q61423	654
Rat	P15385	655

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_012971.3

3127

NP_037103.2

654

Predicted

XM_006234673.4

18549

XP_006234735.1

654

transcript variant X1

isoform X1

XM_006234674.4

18363

XP_006234736.1

654

transcript variant X2

isoform X1

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Post-Translational Modifications

N-glycosylation

Kv1.4 channels are highly glycosylated. The composition of N-glycosylation was shown to affect the trafficking and cell surface expression levels of Kv1.4 channels [2016]

PTM

Position

Type

Modified residue

Phosphoserine; by PKA

Modified residue

122

Phosphoserine

Modified residue

599

Phosphoserine; by PKA

Glycosylation

352

N-linked (GlcNAc...) asparagine

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Structure

Visual Representation of Kv1.4 Structure
Methodology for visual representation of structure available here

Crystal Structure of Kv1.4

Kv1.4 is a typical voltage-gated channel with six transmembrane-spanning domains, one of which (S4) is charged and thought to be the voltage sensor. The N-terminal forms a ball and chain which can occlude the open channel. In the ΔN construct, amino acids 2–146 are deleted, removing the N-terminal and thus N-type inactivation. A lysine-to-tyrosine point mutation on the extracellular side of S6 was made (Kv1.4[K532Y]). This mutation drastically reduces the ability of the channel to undergo C-type inactivation [1611]

A model of the Kv1.4 pore, based on the crystal structure of KcsA, shows that H508 and K532 lie close together. It is suggested that the acidosis-induced increase of C-type inactivation involves the charge on H508 and K532 [1615]

Kv1.4 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	4646.11	source
Mouse	4519.91	source
Rat	5125.93	source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

Single Channel Current

The single-channel conduc- tance of Kv1.4 is much smaller than that of either Kv1.1 or Kv1.6. Ludewig et al 1993 presented current traces which suggested that the outer pore mutation K533Y increases the conductance of Kv1.4 channels at –60 mV. Our data support this finding; however,we have found that this mutation also produces a smaller but sig- nificant (P < 0.001) increase in open-channel conductance at +60 mV both in symmetrical high K+ and in asymmetrical K+. The conductance of Kv1.4 at +60 mV in symmetrical high K+ was increased from ap- prox. 7.8 pS to 10.5 pS

Kv1.4 ion channels undergo inactivation via two distinct mechanisms. N-type inactivation is fast, and, when present, dominates channel closure. C-type inactivation is slower, and is the rate-limiting step controlling the rate of recovery from inactivation. C-type inactivation therefore plays a crucial role in the availability of the channel for the next stimulation in physiological systems [1611]

Kv1.4 Kinetics

Kv1.4 α subunits display: (i) rapid sigmoidal activation kinetics; (ii) biexponential inactivation kinetics; (iii) very slow kinetics of recovery (time constants on the order of seconds); (iv) cumulative inactivation during repetitive voltage clamp pulses; (v) open-state block by 4-AP, and (vi) insensitivity to HPTXs, PaTXs and flecanide [1617]

Kv1.4 in CHO cells is altered by KCNEs

Strikingly, KCNE1 and KCNE2 each significantly increased Kv1.1-Kv1.4 current to a level equivalent to that observed for Kv1.4 when expressed alone. Yet the current displayed the slower inactivation characteristic of Kv1.1-Kv1.4 heteromers. These data suggested that Kv1.1 prevents suppression of Kv1.4 by KCNE subunits, and also that KCNE1 and KCNE2 prevent suppression of Kv1.4 by Kv1.1 [1791]

Kv1.4 channels inactivation measured in Xenopus oocytes and effect of intracellular heme

K+ currents were measured using the inside-out patch-clamp method in Xenopus oocytes expressing Kv1.4. The inactivation constant was 48.2 ± 2.8ms. Application of hemin (200 nM) slowed down the inactivation of Kv1.4 channels to 245 ± 21 ms.[2014]

Kv1.4 inactivation in HEK293T cells and effect of synaptotagmin

Using the patch-clamp technique Kv1.4 currents were measured in HEK293T cells. The inactivation time of Kv1.4 channels was 38.1 ± 2.3 ms at a membrane potential of +30mV. Co expression of synaptotagmin I lead to the N-type fast inactivation of Kv1.4 being delayed to 68.8 ± 2.6 ms in Ca2+ dependent manner.[1609]

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Biophysics

Model Kv1.4 (ID=20)

Kslow modified (V shift of -21mV)

Animal	rat
CellType	Oocyte
Age	0 Days
Temperature	0.0°C
Reversal	-65.0 mV
Ion	K +
Ligand ion
Reference	[274] O Pongs et. al; EMBO J. 1989 Nov
mpower	1.0
m Inf	1.0000/(1+ exp((v - -21.7000)/-16.9000))
m Tau	3.0000
hpower	1.0
h Inf	1.0000/(1+ exp((v - -73.6000)/12.8000))
h Tau	119.0000

MOD - xml - channelML

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Expression and Distribution

Kv1.4 Expression in Brain

Kv1.4 subunit were localized in the AIS of cortical cells in P10 rats.[427]

Kv1.4's expression is time-dependent: The protein expression of the A-type (fast-inactivating) potassium channel Kv1.4 started around P10 in situ in granule cells of the DG, and in neurons of stratum pyramidale of the CA3 area with strongly labeled somata on P12. The expression peaked around P14 and diminished on P15, paralleled by the emerging appearance of Kv1.4-positive staining in the inner molecular layer of DG and in the mossy fiber tract.

Expression related to Kv co-localization

Kv1.1 and Kv1.4 are found robustly expressed in the relative absence of Kv1.2 within the striatal efferents in globus pallidus and pars reticulata of substantial nigra. Kv1.1, Kv1.2, and Kv1.4 are highly expressed in the middle third of the molecular layer of the dentate gyrus where they are associated with axons and terminals of the medial perforant path. Kv1.1, Kv1.2, and Kv1.4 are also found in Schaffer collateral axons, whereas Kv1.1 and Kv1.4 colocalize, in the absence of Kv1.2, in mossy fiber axons [1368].

The onset and development of Kv1.4 protein expression depend on neuronal activity in mouse hippocampal neurons.[378]

The strong expression of Kv1.4 protein in the adult mossy fiber tract underlines the important role in modulating electrophysiological behavior in the mouse hippocampus.[378]

Adrenal zona fasciculata

In the adrenal zona fasciculata Kv1.4, together with Cav3.2 and TREK-1 shape the cellular current properties[2013]

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CNS Sub-cellular Distribution

Distribution in Neuron

Kv1.4 are concentrated along axons and in the axonal membrane immediately preceding or within axon terminals. Immunoreactivity for Kv1.4 has been localized to the preterminal extensions of mossy fiber axons. In these positions, activation of Kv1 channels can play a critical role in regulating the extent of nerve terminal depolarization and thereby regulate neurotransmitter release. [1368]

Strong Kv1.4 signal in mossy fiber axons was seen between P16 and P17. In contrast to the Kv1.2 channel subunit, the strong expression of Kv1.4 in some interneurons of the CA3 area was restricted to their somatodendritic compartment as confirmed by primary cultures of hippocampal CA3 neurons. However, the axonal sorting of Kv1.4 was clearly visible in granule cells in primary cultures from DG. [378]

Kv1.4 Cellular Distribution in the Brain

Phosphorylation of voltage-gated K+ channels (Kv) is involved in regulation of neuronal excitability, synaptic plasticity and neuronal survival. Among Kv channels expressed in the CNS, Kv1.4 is located in the soma, dendrite and axon terminus of neurones in most regions of the brain [1802]

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Function

Function in the neuron

Although Kv1.4 contributes to a presynaptic A–type current to regulate neurotransmitter release [1609]

Fast inactivation of Kv1.4 is modulated by structural elements in the C-terminus.[10]

The expression of Kv1.4 in cortical cells of P10 rats converted the delayed rectifier Kv1.1/Kv1.2 channels to fast inactivating, transient A-type channels. [329]

Spiking properties

Kv1.4 subunits contribute to the late-spiking (LS) properties displayed by small pyramidal neurons in layer 2/3 of rat retrosplenial cortex. These firing properties are a consequence of delayed rectifier and A-type potassium channels, identified as Kv1.4, as well as Kv1.1 and Kv4.3[1891]

Neuronal Excitability

A-type K+ channels encoded by Kv4.2, Kv4.3 and Kv1.4 differentially regulate intrinsic excitability of cortical pyramidal neurons [1798]

Disease

DIABETES

Diabetes slows down Ito recovery of inactivation because it triggers the switching from fast-recovering Kv4.x channels to the slow-recovering Kv1.4 [733]

HYPERTROPHY

The up-regulation of Kv1.4 expression could lead to hypertrophy and heart failure, indicating that the behavior of this channel is of particular clinical importance [1803]

BLADDER HYPER-EXCITABILITY

Results indicate that the excitability of capsaicin sensitive C-fiber bladder afferent neurons is increased in association with reductions in transient A-type K+ current density and Kv1.4 α-subunit expression in injured rats. Thus, the Kv1.4 α-subunit could be a molecular target for treating overactive bladder due to neurogenic detrusor overactivity [1613]

Alzheimer's

The Aβ peptide induces overexpression of Kv1.4 subunits in Alzheimer's. These expression levels could be attenuated in hippocampus and cortex by application of substance P through the cerebrospinal fluid. Indicating a possible neuroprotective activity of substance P[2011]

Myasthenia gravis

Cardiac auto-antibodies against Kv1.4 were implicated in myasthenia gravis [2012]

Circadian clock regulation

Membrane properties of neurons in the suprachiasmatic nucleus (SCN) were shown to feedback to regulate clock (PER2) expression. Kv1.4 and Kv4.2 channels may mediate this regulation of circadian pacemaker (PER2) and light-dependent responses [2015 ]

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Interaction

DPP10

Expressing a dipeptidyl peptidase-related ancillary subunit, DPP10, with Kv1.4 showed faster time to peak current, negative shifts in the half-inactivation potential of steady-state activation and inactivation but slower recovery from inactivation. (Many effects are the same as for DPP10 on Kv4.3) [9]

Propafenone

fKvl.4deltaN channel current was rapidly depressed in a frequency-dependent manner and C-type inactivation was strongly increased in the presence of 100 microM propafenone. While propafenone has no effect on Kv1.4deltaN recovery. [446]

Synaptotagmin I

Synaptotagmin I was found to delay the inactivation of Kv1.4 in HEK293T cells in a Ca2+-dependent manner, and this interaction was proven to have specificity. Mutagenesis experiments indicated that synaptotagmin I interacted with the N-terminus of Kv1.4 and thus delayed its N-type fast inactivation [1609]

Kv1.2

The Kv1.4/Kv1.2 heteromultimer combines features of both parent subunits, resulting in an A-type K+ channel. It has been proposed that both heteromultimers co assemble in the rat brain to regulate neurotransmitter release [733]

Kvβ1

Interestingly, the pattern of immunoreactivity for Kvβ1 closely matches the expression pattern for Kv1.1 and Kv1.4, in that Kvβ1 is found to colocalize with Kv1.4 in the medial perforant path, mossy fiber pathway, and in striatal efferents to the globus pallid us [1368]

Kvβ3

Kv beta 3 slowed recovery from inactivation for Kv1.4, but not for a Kv1.4 deletion mutant lacking N-type inactivation. Finally, steady-state activation and the time course of Kv1.4 current activation were not strongly influenced by Kv beta 3; however, deactivation was slowed in the presence of Kv beta 3 [1616]

Kvβ1.3

Kvβ1.3 accelerates both the fast and slow components of inactivation, promotes the slower component of inactivation and slows recovery of Kv1.4 [1617]

Quinidine

Quinidine is a commonly used anti-arrhythmic agent which blocks K+ channels. Quinidine block of the Kv1.4ΔN channel is a complex process, involving more than one conformational state. Initially, quinidine blocks the open channel with rapid kinetics on the same time scale as activation. Subsequently, the quinidine-bound channel enters a C-type inactivated state in a time- and voltage-dependent manner. Recovery from this state is the same as recovery from C-type inactivation, and governs the use dependence of quinidine block. The apparent dissociation constant for quinidine was reduced by increasing [K+]o to 98 mm (KD = 374.7 μm, n = 9) or a lysine to tyrosine mutation at position 532 [1614]

Arachidonic Acid

Arachidonic acid potently inhibits both postsynaptic-type Kv4.2 and presynaptic-type Kv1.4 IA potassium channels [1799]

Ginsenoside

We have demonstrated previously that the 20(S) but not the 20(R) form of ginsenoside Rg(3) inhibited K(+) currents flowing through Kv1.4 (hKv1.4) channels expressed in Xenopus laevis oocytes, pointing to the presence of specific interaction site(s) for Rg(3) in the hKv1.4 channel [1800]

Curcumin

Curcumin, a major constituent of the spice turmeric, is a nutriceutical compound reported to possess therapeutic properties against a variety of diseases ranging from cancer to cystic fibrosis. In whole-cell patch-clamp experiments on bovine adrenal zona fasciculata (AZF) cells, curcumin reversibly inhibited the Kv1.4K+ current with an IC50 of 4.4 microM and a Hill coefficient of 2.32. Inhibition by curcumin was significantly enhanced by repeated depolarization; however, this agent did not alter the voltage-dependence of steady-state inactivation [1801]

Intracellular heme

Heme interacts with N-terminal inactivation domain of Kv1.4 channels. A process that enables intracellular free heme to potently impair Kv1.4 ball-and-chain inactivation [2014]

Heteromeric Interaction Kv1.4 and Kv1.1

The membrane potential of spiral ganglion neurons (SGN) of Kcna2 null mice was significantly hyperpolarized compared with that of wild-type SGNs. It was suggested that heteromultimerization of Kv1.2 and Kv1.4 α-subunits defines the properties of SGNs [1604]

Hydrogensulfate

Nociceptive processing in trigeminal ganglion (TG) neurons involves endogenous H2S generating enzyme (CBS) co-localization with Kv1.1 and Kv1.4. Application of NaHS, an H2S donor, supresses IK density with impact on neuronal excitability[1893]