Kv4.2
Description: potassium voltage-gated channel, Shal-related subfamily, member 2 Gene: Kcnd2 Synonyms: Kv4.2, kcnd2, Shal1, RK5
Potassium voltage-gated channel subfamily D member 2 is a protein that in humans is encoded by the KCND2 gene. It encodes KV4.2 (also known as RK5; KIAA1044; MGC119702; MGC119703) which contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential. This rapidly inactivating, A-type outward potassium current is not under the control of the N terminus as it is in Shaker channels.
http://en.wikipedia.org/wiki/Kv4.2 http://www.ncbi.nlm.nih.gov/gene/3751
Experimental data
Rat Kv4.2 gene in CHO host cell datasheet |
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Gene
Transcript
Ontology
Accession | Name | Definition | Evidence | |||||||
---|---|---|---|---|---|---|---|---|---|---|
GO:0005886 | plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. | IDA | |||||||
GO:0005887 | integral to plasma membrane | Penetrating at least one phospholipid bilayer of a plasma membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. | IDA | |||||||
GO:0008076 | voltage-gated potassium channel complex | A protein complex that forms a transmembrane channel through which potassium ions may cross a cell membrane in response to changes in membrane potential. | IDA | |||||||
GO:0030425 | dendrite | A neuron projection that has a short, tapering, often branched, morphology, receives and integrates signals from other neurons or from sensory stimuli, and conducts a nerve impulse towards the axon or the cell body. In most neurons, the impulse is conveyed from dendrites to axon via the cell body, but in some types of unipolar neuron, the impulse does not travel via the cell body. | IDA | |||||||
GO:0043025 | neuronal cell body | The portion of a neuron that includes the nucleus, but excludes all cell projections such as axons and dendrites. | IDA | |||||||
GO:0009986 | cell surface | The external part of the cell wall and/or plasma membrane. | IEA | |||||||
GO:0019717 | synaptosome | Any of the discrete particles (nerve-ending particles) formed from the clublike presynaptic nerve endings that resist disruption and are snapped or torn off their attachments when brain tissue is homogenized in media isosmotic to plasma. | IDA | |||||||
GO:0014069 | postsynaptic density | The post synaptic density is a region that lies adjacent to the cytoplasmic face of the postsynaptic membrane at excitatory synapse. It forms a disc that consists of a range of proteins with different functions, some of which contact the cytoplasmic domains of ion channels in the postsynaptic membrane. The proteins making up the disc include receptors, and structural proteins linked to the actin cytoskeleton. They also include signalling machinery, such as protein kinases and phosphatases. | IDA | |||||||
GO:0043197 | dendritic spine | Protrusion from a dendrite. Spines are specialised subcellular compartments involved in the synaptic transmission. They are linked to the dendritic shaft by a restriction. Because of their bulb shape, they function as a biochemical and an electrical compartment. Spine remodeling is though to be involved in synaptic plasticity. | IDA | |||||||
GO:0016020 | membrane | Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. | IEA |
High External Potassium Concentration
High external potassium concentration counteracts Shaker C-type inactivation [479] and accelerates Kv4 channel inactivation [24], [418].
KCNE3
KCNE3 may regulate the activity of Kv4.2 channels in SGNs. At least one of the Kv channels, under the regulation of KCNE3, would generate a transient current. Among the transient current channels in SGNs is Kv4.2. We expressed mouse Kv4.2 in Chinese Hamster Ovarian (CHO) cells, either singly or co-jointly with KCNE3. As expected, transfection of Kv4.2 alone yielded robust transient K+ current.
Transfection of Kv4.2 and KCNE3, at different ratios, resulted in whole-cell K+ current with reduced transient, but increased sustained components. A crosscheck was then completed on Kv4.2 and KCNE3 expression and localization in SGNs. SGNs reacted positively to antibodies against Kv4.2 and KCNE3, and the two proteins were co-localized. In contrast, we did not detect positive staining with antibodies against Kv4.3, consistent with the results of previous studies [1685]
KChIP1b and KChIP1a
The potassium channel interacting protein KChIP1b splice variant induces slow recovery from inactivation for Kv4.2 whereas KChIP1a enhanced the recovery. Reduction of the side chain bulkiness in exon1b resulted in the conversion of the KChIP1b phenotype into the KChIP1a phenotype. [31]
Calcium–calmodulin-dependent kinase II (CaMKII)
CaMKII can directly modulate neuronal excitability by increasing cell-surface expression of A-type K+ channels (Kv4.2). CaMKII phosphorylation had no effect on channel biophysical properties. [32]
DPPX (DPP6) and DPP10
Dipeptidyl aminopeptidase-like protein DPPX (DPP6) associates with Kv4 potassium channels, increasing surface trafficking and reconstituting native neuronal ISA-like properties. Coexpression of dipeptidyl peptidase 10 (DPP10) and HA-tagged DPP10 enhanced Kv4.2 current approximately fivefold without increasing protein level. [33]
Cytochalasin D
Distribution and density of Kv4.2 channels at the cell surface are primarily the result of reorganization of the actin cytoskeleton. Pretreatment of HEK cells with cytochalasin D to disrupt the actin microfilaments greatly augmented whole cell Kv4.2 currents at potentials positive to 20 mV. [34]
PrPC
Following a rapid rise to peak amplitude, the current rapidly decayed despite a continued depolarizing step command. In the presence of exogenous PrPC, the peak amplitude of the A-type K+ currents at 20 mV was larger (14.5 ± 0.9 nA; average ± S.E., n = 17) than that mediated by the Kv4.2 channel complex in its absence [1669]
KChiP1, 2 , 3
The following table emphasizes the effects of KChiPs on the Kv4 family [1195]
Protein
Structure
Crystal Structure
Tetraemic complexes of subunits
Kv4 potassium channels, like voltage-gated K+ channels, are formed from tetrameric complexes of identical or genetically related α-subunits from the same subfamily. All Kv α-subunits possess a cytoplasmic amino-terminal region, six transmembrane segments (S1–S6) plus their associated interconnecting intracellular and extracellular loops, and a cytoplasmic carboxy-terminal region. The S1–S6 region, known as the “core”, conducts the main businesses of potassium selectivity, ion conduction, and voltage-dependent gating. The S5 and S6 segments form the innermost structures and line the pore region through which K+ must traverse down its electrochemical gradient across the membrane. The S5–S6 loop, or pore (P)-loop, sits at the outer end of the “inverted teepee” formed by S5 and S6 segments from all four α-subunits and acts as the selectivity filter [467]
DISTRIBUTION IN NEURON
Kv4.2 is abundant in the dendrites of CA1 pyramidal neurons of the hippocampus.[293]. Kv4.2 and Kv4.3 are expressed in membranes of somata, dendrites, and spines of pyramidal cells and GABAergic neurons. [319]
KChIP2 co-localizes with Kv4.2 in the dendrites of granule cells in the dentate gyrus (Fig. 3d–f), in the apical and basal dendrites of hippocampal and neocortical pyramidal cells, and in several subcortical structures including the striatum and thalamus [1195]
Immunocytochemical studies have shown that the subcellular distribution of neuronal rat Kv4.2 channels is restricted to the somatodendritic area, and the high abundance of Kv4.2 in the soma and dendrites led to the hypothesis that these channels may have an important influence on postsynaptic neuronal signal transduction [1686]
Immunohistochemical analysis shows that Kv4.2 has a somatodendritic distribution, and in adult hippocampus, Kv4.2 is expressed on distal dendrites and neuropils of CA1-3 neurons. The somatodendritic membrane of rat neostriatal cholinergic interneurons express Kv4.2 but not Kv1.4 according to immunocytochemical analysis [467]
Expression in mouse brain
Kv4.2 can be found in pyramidal neurons in mouse neocortex. [319]
Kv4.2 is concentrated within the perinuclear endoplasmic reticulum and Golgi compartments, with some immunoreactivity apparent at the outer margins of the cell (Fig. 3b). When KChIP1 is expressed with Kv4.2, the characteristic diffuse KChIP1 distribution changes markedly, such that KChIP1 and Kv4.2 immunofluorescence completely overlap [1195]
KV4.2 FUNCTION IN NEURON
In hippocampal pyramidal neurons, where the A-type channel density increases with distance from the soma, activation of Kv4.2 channels may prevent the back-propagation of action potentials. In addition, the rapid activation of A-type channels may protect the postsynaptic membrane from excessive depolarization [1687]
Inactivation of Kv4.2 channels by subthreshold EPSPs can lead to spike amplification, which provides a possible explanation for the Hebbian associativity found in distal dendrites [1688]
PROLONGING INHIBITION IN SYNAPTIC TRANSMISSION
More recently it has been shown that A-type channels localized to the dendritic spines of GABAergic interneurons in the olfactory bulb are necessary to counterbalance fast glutamatergic EPSPs, thereby allowing a prolonged inhibitory synaptic transmission in a local feedback loop. The inhibitory synaptic transmission becomes shorter and stronger when the A-type channels are inactivated by subthreshold membrane depolarization [1689]
Fragile X Syndrome, Mental Retardation
FMRP is a positive regulator of Kv4.2 mRNA translation and protein expression and associates with Kv4.2 mRNA in vivo and in vitro. Our results suggest that absence of FMRP-mediated positive control of Kv4.2 mRNA translation, protein expression, and plasma membrane levels might contribute to excess neuronal excitability in Fmr1 KO mice, and thus imply a potential mechanism underlying FXS-associated epilepsy [1827]
Neurological Disorders
Neuronal excitability is tightly regulated, and defects in mechanisms involved in this regulation can lead to neurological disorders. A key player in the control of neuronal excitability in the brain is the A-type potassium channel Kv4.2. This potassium channel controls excitatory currents in the hippocampus and is thus critical to maintain a healthy excitatory balance in the brain. Emerging data suggests that Kv4.2 protein levels are dysregulated in a variety of disease states. (http://www.ibridgenetwork.org/emory/oligonucleotide-antagonists-of-kv4-2-regulating-micrornas-mir)
Kv4.2 not involved in Neuropsychiatry
We did not find clear evidence for an involvement of Kv4.2 in neuropsychiatric or plasticity-related phenotypes, but there was support for a role in Kv4.2 in dampening excitatory responses to novel stimuli [1828]
Cardiomyopathy and Heart Failure
cardiac-specific (driven by +/-MHC promoter) overexpression of a dominant-negative Kv4.2 K+ channel subunit in mice caused dilated cardiomyopathy and heart failure, in addition to prolongation of action potential duration (APD) [1829]
Kv4.2 Kinetics
rat Kv4.2 expressed in CHO
[1195]
As the KChIPs localize and associate with native Kv4 alpha-subunits, it was determined whether they modulate the electrophysiological properties of expressed Kv4 channels. Transient transfection of the rat Kv4.2 alpha-subunit in CHO cells yielded typical A-type potassium currents. Expression of Kv4.2 together with KChIP1, 2 or 3 revealed several effects of KChIP co-expression on Kv4 currents. First, the density of Kv4.2 currents increased about 12-fold, indicating that KChIP1 may promote and/or stabilize expression of Kv4.2 at the cell surface. Second, the midpoint of voltage activation of Kv4.2 currents shifted to more hyperpolarized potentials. Furthermore, the kinetics of Kv4.2 inactivation slowed considerably, whereas KChIP/Kv4.2 channels recovered from inactivation much more rapidly versus channels produced by Kv4.2 expression alone [1195]
DELETION of AMINO ACIDS ALTERS EXPERESSION
Deletions in the first 40 amino acids of the Kv4 alpha subunit N-terminus significantly increase the functional expression of Kv4.2 channels and eliminate KChIP regulation
INTERACTION WITH KCHiP
Transient transfection of the rat Kv4.2 alpha-subunit in CHO cells yielded typical A-type potassium currents. Expression of Kv4.2 together with KChIP1, 2 or 3 revealed several effects of KChIP co-expression on Kv4 currents. First, the density of Kv4.2 currents increased about 12-fold, indicating that KChIP1 may promote and/or stabilize expression of Kv4.2 at the cell surface. Second, the midpoint of voltage activation of Kv4.2 currents shifted to more hyperpolarized potentials. Furthermore, the kinetics of Kv4.2 inactivation slowed considerably, whereas KChIP/Kv4.2 channels recovered from inactivation much more rapidly versus channels produced by Kv4.2 expression alone [1195]
Model
Kinetic Model based on Markov Model for Kv4.2
Predictions of a Kv4.1 kinetic model with adjusted parameters for Kv4.2. The K+ channel state diagram used for these simulations includes inactivation both from a pre-open closed state (C4→ IC) and from the open state (O → IO). The closed-state inactivation also accesses a deeper inactivated state (ID). Transitions between states are represented by arrows [30]
Model Kv4.2 (ID=40) Edit - History
Tau is modified(multipled by 0.2) from model1
Animal | rat | |
CellType | Neocortical L5PC | |
Age | 14 Days | |
Temperature | 23.0°C | |
Reversal | -68.7 mV | |
Ion | K + | |
Ligand ion | ||
Reference | J M Bekkers et. al; J. Physiol. (Lond.) 2000 Jun 15 | |
mpower | 3.0 | |
m Inf | (1/(1 + exp((v- -18.8)/-16.6))) | |
m Tau | 1.0/((0.026* exp(-0.026*v)) + (35* exp(0.136*v))) If v lt -50 | |
m Tau | 1.7/(1+ exp((-42 - v)/-26)) + 0.34 If v gteq -50 | |
hpower | 1.0 | |
h Inf | 1/(1 + exp((v - -81.6)/6.7)) | |
h Tau | 0.01*v + 6.7 |
References
28
Dougherty K
et al.
Gating charge immobilization in Kv4.2 channels: the basis of closed-state inactivation.
J. Gen. Physiol.,
2008
Mar
, 131 (257-73).
29
Barghaan J
et al.
Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels.
J. Gen. Physiol.,
2009
Feb
, 133 (205-24).
Van Hoorick D
et al.
The aromatic cluster in KCHIP1b affects Kv4 inactivation gating.
J. Physiol. (Lond.),
2007
Sep
15
, 583 (959-69).
Varga AW
et al.
Calcium-calmodulin-dependent kinase II modulates Kv4.2 channel expression and upregulates neuronal A-type potassium currents.
J. Neurosci.,
2004
Apr
7
, 24 (3643-54).
Jerng HH
et al.
Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10).
Biophys. J.,
2004
Oct
, 87 (2380-96).
Wang Z
et al.
Increased focal Kv4.2 channel expression at the plasma membrane is the result of actin depolymerization.
Am. J. Physiol. Heart Circ. Physiol.,
2004
Feb
, 286 (H749-59).
35
Sanguinetti MC
et al.
Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels.
Mol. Pharmacol.,
1997
Mar
, 51 (491-8).
Kim J
et al.
Regulation of dendritic excitability by activity-dependent trafficking of the A-type K+ channel subunit Kv4.2 in hippocampal neurons.
Neuron,
2007
Jun
21
, 54 (933-47).
295
Nerbonne JM
et al.
Electrical remodelling maintains firing properties in cortical pyramidal neurons lacking KCND2-encoded A-type K+ currents.
J. Physiol. (Lond.),
2008
Mar
15
, 586 (1565-79).
296
Bekkers JM
Properties of voltage-gated potassium currents in nucleated patches from large layer 5 cortical pyramidal neurons of the rat.
J. Physiol. (Lond.),
2000
Jun
15
, 525 Pt 3 (593-609).
Burkhalter A
et al.
Differential expression of I(A) channel subunits Kv4.2 and Kv4.3 in mouse visual cortical neurons and synapses.
J. Neurosci.,
2006
Nov
22
, 26 (12274-82).
328
Serôdio P
et al.
Differential expression of Kv4 K+ channel subunits mediating subthreshold transient K+ (A-type) currents in rat brain.
J. Neurophysiol.,
1998
Feb
, 79 (1081-91).
Baukrowitz T
et al.
Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms.
Neuron,
1995
Oct
, 15 (951-60).
Jerng HH
et al.
Inactivation gating of Kv4 potassium channels: molecular interactions involving the inner vestibule of the pore.
J. Gen. Physiol.,
1999
May
, 113 (641-60).
480
Kaulin YA
et al.
Mechanism of the modulation of Kv4:KChIP-1 channels by external K+.
Biophys. J.,
2008
Feb
15
, 94 (1241-51).
Mercer RC
et al.
The prion protein modulates A-type K+ currents mediated by Kv4.2 complexes through dipeptidyl aminopeptidase-like protein 6.
J. Biol. Chem.,
2013
Dec
27
, 288 (37241-55).
Wang W
et al.
Functional Significance of K+ Channel β-Subunit KCNE3 in Auditory Neurons.
J. Biol. Chem.,
2014
Apr
11
, ().
1197
Bähring R
et al.
Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating.
J. Biol. Chem.,
2001
Jun
29
, 276 (23888-94).
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).
Sheng M
et al.
Subcellular segregation of two A-type K+ channel proteins in rat central neurons.
Neuron,
1992
Aug
, 9 (271-84).
Hoffman DA
et al.
K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.
Nature,
1997
Jun
26
, 387 (869-75).
Magee JC
et al.
A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons.
Science,
1997
Jan
10
, 275 (209-13).
Schoppa NE
et al.
Regulation of synaptic timing in the olfactory bulb by an A-type potassium current.
Nat. Neurosci.,
1999
Dec
, 2 (1106-13).
An WF
et al.
Modulation of A-type potassium channels by a family of calcium sensors.
Nature,
2000
Feb
3
, 403 (553-6).
Gross C
et al.
Fragile X mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4.2.
J. Neurosci.,
2011
Apr
13
, 31 (5693-8).
Kiselycznyk C
et al.
Effects of genetic deletion of the Kv4.2 voltage-gated potassium channel on murine anxiety-, fear- and stress-related behaviors.
Biol Mood Anxiety Disord,
2012
, 2 (5).
Guo W
et al.
Molecular basis of transient outward K+ current diversity in mouse ventricular myocytes.
J. Physiol. (Lond.),
1999
Dec
15
, 521 Pt 3 (587-99).
Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna
To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/ionchannels/16/ , accessed on [date]