Kv4.2

Description: potassium voltage-gated channel, Shal-related subfamily, member 2
Gene: Kcnd2 Synonyms: Kv4.2, kcnd2, Shal1, RK5

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Introduction

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

RGD ID	Chromosome	Position	Species
68393	4	47541787-48047924	Rat
68575	6	21166109-21679805	Mouse
68574	7	119913722-120390387	Human

Kcnd2 : potassium voltage-gated channel, Shal-related subfamily, member 2

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Transcript

Acc No	Sequence	Length	Source
NM_031730	n/A	n/A	NCBI
NM_019697	n/A	n/A	NCBI
NM_012281	n/A	n/A	NCBI

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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

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Interaction

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]

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Protein

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Structure

Crystal Structure

Kv3.1 Expression

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]

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Distribution

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]

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Expression

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]

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Functional

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]

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Kinetics

Kv4.2 Kinetics

[1669]

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]

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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(-0.026v)) + (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