Channelpedia

Kv4.1

Description: potassium voltage-gated channel, Shal-related subfamily, member 1
Gene: Kcnd1
Alias: Kv4.1, kcnd1, Kca2-1, mShal1, Shal

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Introduction

Kv4.1, encoded by the gene KCND1, is a member of the potassium voltage-gated channel subfamily D. Kv4.1 plays a role in the repolarization phase of the action potential. Kv4.1 is expressed at moderate levels in all tissues analyzed, with lower levels in skeletal muscle.NCBI

Experimental data

Rat Kv4.1 gene in CHO host cells       datasheet

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Gene

Species NCBI gene ID Chromosome Position
Human 3750 X 10464
Mouse 16506 X 17610
Rat 116695 X 17057
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Transcript

Species NCBI accession Length (nt)
Human NM_004979.6 4718
Mouse NM_008423.2 3815
Rat NM_001105748.1 3712
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Protein Isoforms

Species Uniprot ID Length (aa)
Human Q9NSA2 647
Mouse Q03719 651
Rat D3ZYK3 650

Isoforms

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Length (nt)
Protein
Length (aa)
Variant
Isoform
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Post-Translational Modifications

PTM
Position
Type
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Structure

Kv4.1
Visual Representation of Kv4.1 Structure
Methodology for visual representation of structure available here

Stereo view of binding site in T1 domain of Kv4.1

Kv4.1 structure

Kv4.1 binding site A stick representation of the coordinating residues is shown. C131, C132 and H104 are from the same subunit, and C110 is from the neighboring subunit. The blue sphere represents a Zn2+ ion in the binding site. Although the isolated T1 domain oligomer is typically Zn2+-bound, the T1 domain in the intact Kv4.1 channel appears to be Zn2+-free or partially liganded [1562]

Kv Proteins have a core membrane consisting of six putative membrane- spanning domains designated S1, S2, S3, S4, S5, and S6 flanked by intracellular amino and carboxyl domainsof vari- able lengths, and an H5 or pore (P) domain (between the S5 and S6 membranespanning sequences)thought to contribute to the channel’s pore. The amphipatic S4 domain is believed to be a key part of the voltage sensor and has a number of positively charged residuesthat is characteristic for each subfamily of proteins (5 in Shal subunits) [395]

Kv4.1 predicted AlphaFold size

Species Area (Å2) Reference
Human 7147.33 source
Mouse 5226.14 source
Rat 4690.42 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

Single Channel Conductance

Kv4.1 In the presence of KChIP1, the development of inactivation underwent a significant transformation. Specifically, the early phase of the current decayed more slowly [25]

Channel Kinetics with and without KChip1

Kv4.1 Upon depolarization, control currents exhibited characteristic rapid activation and slower inactivation. At positive voltages, the kinetics of inactivation were complex and included fast and slow phases. Typically, depolarizations > 1 s were necessary to nearly reach the zero-current level [25]

Although Kv4.1 and Kv4.2 share high sequence similarity, KChIP1 has opposite effects on their voltage dependence of activation and the inactivation time courses. KChIP1 slows Kv4.2 inactivation but accelerates the Kv4.1 inactivation time course [1563]

Homomeric channels arising from Kv1.4, Kv3.4, and Kv4.1, Kv4.2, and Kv4.3 subunits give rise to A-type channels [274], [636], [635], [395].

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Biophysics

Kinetic Model

Kv4.1

The two main kinetic features of Model 1 are, first, that Kv4.1 channels have to return from the short-lived open-inactivated state IO via the open state to the pre-open closed state before they can enter the closed-inactivated state, IC, and second, that cumulative Kv4.1 channel inactivation is a two-step reaction involving the closed-inactivated state, IC, and the deep-inactivated state, ID [30]

Markov Model Kv4.1

Kv4.1

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Expression and Distribution

Kv channels have been considered important in excitable cells such as neurons and myocytes where they are involved in the regulation of membrane potential, and the generation and propagation of action potentials. [637], [638], [639], [640], [556]. However, several subtypes of Kv channels are also expressed in non-excitable cells such as epithelial cells, where they contribute to cell migration and wound healing, O2 sensing, cell proliferation, and apoptosis.[641], [642], [643], [644].

Kv4.1, one member of the Kv channel family, was originally cloned from brain tissue, [645] where it exists at a low level [395]. According to several recent reports, Kv4.1 mRNA and protein have been detected in epithelial cells, including alveolar and mammary epithelial cells and adipose tissue-derived stem cells. [397], [646] ,[647].

Kv4.1 mRNA-positive cells represented 59.5 % of DRG (dorsal root ganglion) neurons [1561]

In this study, we found that Kv4.1 and Kv4.2 channel subunits of the Shal-related family were expressed in the SCN (suprachiasmatic nucleus) [1566]

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CNS Sub-cellular Distribution

These results argue that the depolarization-activated somatodendritic K+ currents in cholinergic interneurons are dominated by Kv4.2- and Kv4.1-containing channels [26]

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Function

Striatal cholinergic interneurons coexpress several of the alpha and beta subunits known to produce A-type channels but, within the somatodendritic membrane, Kv4.2 and Kv4.1 channels are the predominate channel types and possess the biophysical properties necessary to regulate repetitive discharge. [26]

CANCERS

Kv4.1 expression was proven in breast cancer cells and it is thought to play a role in cell proliferation.[397]

Kv4.1 mRNA and protein are expressed in the human gastric cancer cell lines MKN-45 and SNU-638 and breast cancer cells [397]

Silencing of Kv4.1 expression with siRNA-Kv4.1 inhibited cell proliferation of tumorigenic M13SVR2 and M13SV1R2-N1 cells, but not immortal M13SV1 cells. Although the involvement of Kv4.1 channel subtypes in tumor cell proliferation has not been extensively investigated, a recent study demonstrated that Kv4 may play a role in tumorigenesis of pituitary adenomas [643]

Oxygen regulators

Furthermore, several lines of evidence support the conclusion that Kv4 channel subfamily members (either Kv4.3 alone or Kv4.3/Kv4.1 heteromultimers) are the oxygen sensitive K channels (K(o2)) in rabbit CB chemoreceptor cells [1567]

Regulatory Volume Decrease

Kv4.1 and (or) Kv4.3 play a crucial role in mediating this RVD response [1568]

In the nervous system, Kv4 channels prevent backpropagating action potentials, help to establish slow repetitive spike firing and contribute to spike repolarization and signal amplification [25]

Alzheimers Disease

Changes in Kv4.x channels may also occur in Alzheimer's disease. Mutations in presenilins have been linked to early-onset, autosomal dominant familial Alzheimer's disease [466]

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Interaction

KChIP1

Caused a small but significant depolarizing shift in Kv4.1 activation and KChIP1 markedly accelerated Kv4.1 inactivation. [1563]

Frequenin

Frequenin had relatively modest effects on Kv4.1 currents. Although in some batches of oocytes frequenin increased Kv4.1 current amplitudes, the overall effect was not statistically significant and the inactivation kinetics were largely unaffected. Curve fitting of Kv4.1 current traces to a sum of three exponentials showed that frequenin affected neither the time constants nor the relative contribution of inactivation components [1564]

Jingzhaotoxin-XII

Jingzhaotoxin-XII (JZTX-XII), a 29-residue polypeptide, was purified from the venom of the Chinese tarantula Chilobrachys jingzhao. Electrophysiological recordings carried out in Xenopus laevis oocytes showed that JZTX-XII is specific for Kv4.1 channels, with the IC50 value of 0.363 μM

Heteropoda toxin 2

(HpTx2) is an inhibitor cysteine knot peptide toxin specific for Kv4 channels. HpTx2 interaction with Kv4.1 is considerably less voltage-dependent, has smaller shifts in the voltage-dependences of conductance and steady-state inactivation, and a 3-fold higher K(d) value than Kv4.3 [1565]

DPPX

Here, we explore the presence and functional contribution of DPPX to K(o2) currents (4.1/4.3) in rabbit CB chemoreceptor cells by using DPPX functional knockdown with siRNA. Our data suggest that DPPX proteins are integral components of K(o2) currents, and that their association with Kv4.1 subunits modulate the pharmacological profile of the heteromultimers [1567]

Estrogen

We found that EB significantly increased the expression of Kv4.1 in the rostral arcuate. In the caudal arcuate, EB also increased the expression of Kv4.1 [1569]

sBmTX3

The rapidly activating and inactivating Kv4.1 current was inhibited by sBmTX3, a chemically synthesized toxin originally purified from the venom of the scorpion Buthus martensi (IC50, 105 nM) [1570]

Arachidonic Acid

Arachidonic acid (20uM) selectively inhibits Kv4.1 by almost 50% [1572]

References

25

Beck EJ et al. Remodelling inactivation gating of Kv4 channels by KChIP1, a small-molecular-weight calcium-binding protein.
J. Physiol. (Lond.), 2002 Feb 1 , 538 (691-706).

30

Bähring R et al. Kinetic analysis of open- and closed-state inactivation transitions in human Kv4.2 A-type potassium channels.
J. Physiol. (Lond.), 2001 Aug 15 , 535 (65-81).

397

Kim HJ et al. Involvement of Kv4.1 K(+) channels in gastric cancer cell proliferation.
Biol. Pharm. Bull., 2010 , 33 (1754-7).

466

Birnbaum SG et al. Structure and function of Kv4-family transient potassium channels.
Physiol. Rev., 2004 Jul , 84 (803-33).

556

Miller C An overview of the potassium channel family.
Genome Biol., 2000 , 1 (REVIEWS0004).

635

Schröter KH et al. Cloning and functional expression of a TEA-sensitive A-type potassium channel from rat brain.
FEBS Lett., 1991 Jan 28 , 278 (211-6).

637

Armstrong CM Voltage-gated K channels.
Sci. STKE, 2003 Jun 24 , 2003 (re10).

638

Jan LY et al. Voltage-gated and inwardly rectifying potassium channels.
J. Physiol. (Lond.), 1997 Dec 1 , 505 ( Pt 2) (267-82).

639

Pichon Y et al. Some aspects of the physiological role of ion channels in the nervous system.
Eur. Biophys. J., 2004 May , 33 (211-26).

640

Yellen G The voltage-gated potassium channels and their relatives.
Nature, 2002 Sep 5 , 419 (35-42).

641

O'Grady SM et al. Molecular diversity and function of voltage-gated (Kv) potassium channels in epithelial cells.
Int. J. Biochem. Cell Biol., 2005 Aug , 37 (1578-94).

642

Lotz MM et al. K+ channel inhibition accelerates intestinal epithelial cell wound healing.
, 2004 Sep-Oct , 12 (565-74).

643

Jang SH et al. Silencing of Kv4.1 potassium channels inhibits cell proliferation of tumorigenic human mammary epithelial cells.
Biochem. Biophys. Res. Commun., 2009 Jun 26 , 384 (180-6).

645

Pak MD et al. mShal, a subfamily of A-type K+ channel cloned from mammalian brain.
Proc. Natl. Acad. Sci. U.S.A., 1991 May 15 , 88 (4386-90).

647

Bai X et al. Electrophysiological properties of human adipose tissue-derived stem cells.
Am. J. Physiol., Cell Physiol., 2007 Nov , 293 (C1539-50).

1562

Covarrubias M et al. The neuronal Kv4 channel complex.
Neurochem. Res., 2008 Aug , 33 (1558-67).

1564

Nakamura TY et al. A role for frequenin, a Ca2+-binding protein, as a regulator of Kv4 K+-currents.
Proc. Natl. Acad. Sci. U.S.A., 2001 Oct 23 , 98 (12808-13).

1566

Itri JN et al. Circadian regulation of a-type potassium currents in the suprachiasmatic nucleus.
J. Neurophysiol., 2010 Feb , 103 (632-40).

1567

Colinas O et al. DPPX modifies TEA sensitivity of the Kv4 channels in rabbit carotid body chemoreceptor cells.
Adv. Exp. Med. Biol., 2009 , 648 (73-82).

1568

Harron SA et al. Volume regulation in the human airway epithelial cell line Calu-3.
Can. J. Physiol. Pharmacol., 2009 May , 87 (337-46).

1569

Roepke TA et al. Estrogen regulation of genes important for K+ channel signaling in the arcuate nucleus.
Endocrinology, 2007 Oct , 148 (4937-51).

1572

Villarroel A et al. Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid.
J. Neurosci., 1996 Apr 15 , 16 (2522-32).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/15/ , accessed on 2024 Apr 27