Kv4.1
Description: potassium voltage-gated channel, Shal-related subfamily, member 1 Gene: Kcnd1 Alias: Kv4.1, kcnd1, Kca2-1, mShal1, Shal
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
Transcript
Species | NCBI accession | Length (nt) | |
---|---|---|---|
Human | NM_004979.6 | 4718 | |
Mouse | NM_008423.2 | 3815 | |
Rat | NM_001105748.1 | 3712 |
Protein Isoforms
Isoforms
Post-Translational Modifications
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
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
Methodology for AlphaFold size prediction and disclaimer are available here
Single Channel Conductance
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
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].
Kinetic Model
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
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]
These results argue that the depolarization-activated somatodendritic K+ currents in cholinergic interneurons are dominated by Kv4.2- and Kv4.1-containing channels [26]
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]
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]
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Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna, Katherine Johnston
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