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Kv10.1

potassium voltage-gated channel, subfamily H (eag-related), member 1
Synonyms: Kv10.1 EAG EAG1 h-eag MGC142269 KCNH1. Symbol: Kcnh1

Introductions


The human ether à-go-go1 protein (Eag1, KV10.1, encoded by KCNH1) is a voltage-gated potassium channel and is a member of the EAG family. It is expressed almost exclusively in brain tissue and is involved in cell excitability, memory processes, and cell proliferation [1509] KV10.1 potassium channels are implicated in a variety of cellular processes including cell proliferation and tumour progression. Their expression in over 70% of human tumours makes them an attractive diagnostic and therapeutic target [1509] The gene KCNH1 (also known as EAG; EAG1; h-eag; Kv10.1; MGC142269) encodes Kv10.1, a potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. [648]

Genes


Human and rat Kv10.1a and b cDNAs encode silent K+ channel pore-forming subunits that modify the electrophysiological properties of Kv2.1. These alternatively spliced variants arise by the usage of an alternative site of splicing in exon 1 producing an 11-amino acid insertion in the linker between the first and second transmembrane domains in Kv10.1b. [675].

Kcnh1 : potassium voltage-gated channel, subfamily H (eag-related), member 1

RGD ID Chromosome Position Species
68398 13 108129617-108407815 Rat
68585 1 194014754-194334040 Mouse
68584 1 210851657-211307457 Human

Transcripts


Acc No Sequence Length Source
NM_031742 NCBI
NM_010600 NCBI
NM_001038607 NCBI
NM_172362 NCBI
NM_002238 NCBI

Ontologies


Accession Name Definition Evidence

Interactions


Kv2.1

Human and rat Kv10.1a and b cDNAs encode silent K+ channel pore-forming subunits that modify the electrophysiological properties of Kv2.1. Co-injection of Kv2.1 and Kv10.1a or b mRNAs in Xenopus oocytes produced smaller currents that in the Kv2.1 injected oocytes and a moderate reduction of the inactivation rate without any appreciable change in recovery from inactivation or voltage dependence of activation or inactivation [675]

Magnesium

Kv1.1 structure [778]

Activation kinetics depend on the holding potential and the extracellular Mg eag1-like membrane currents were elicited in a human neuroblastoma cell in response to depolarizations to 50 mV from holding potentials which varied from −130 to −40 mV in steps of 10 mV in external solutions containing the indicated concentrations of Mg2+ or 50




Calcium induces block in CHO cells

Kv1.1 structure [778] Ca -induced block of rat eag1 channels heterologously expressed in CHO cells. Steady-state channel activity measured in inside-out patches at 0 mV in the presence of 30 nM free [Ca2+ ], after changing to a solution with 150 nM free [Ca2+ ] and on return to 30 nM free [Ca2+]

Hyperkinetic B-subunit

So far, a few B-subunits have been found to interact with eag1 channels and to affect their biophysical properties. The Drosophila B-subunit hyperkinetic increases the current amplitude mediated by Drosophila eag1 chan- nels, slightly accelerates current activation and slows inactivation [1717]

EPSIN

The protein epsin was isolated from rat brain and has been found to bind to eag1 channels, thereby decreasing the probability of channel opening at potentials near the resting potential [1718]

KCR1

Binding of the protein KCR1 to eag channels leads to an increase in the eag current amplitude by induction of a faster eag channel activation and a shift of the activation curve by 10 mV to more negative membrane potentials [1719]

ICA

Kv1.1 structure ICA strongly inhibits inactivation and thereby increases the magnitude of hERG1 channel currents (same family as EAG1), especially at positive potentials [1510]. The effects of this compound (ICA) on hEAG1, were tested with the expectation that it might also inhibit intrinsic inactivation and increase current magnitude. Instead, we found that ICA appeared to enhance inactivation of hEAG1. [1504]




Mutation

Mutation of Tyr652 in S6 segment enhances hEAG1 channel inactivation [1504]

Proteins


Rabaptin-5, an effector of the Rab5 GTPase, co-localize on large early endosomes induced by Rab5 hyperactivity [1513]

Structures


Crystal Structure of EAG (Kv10.1) channel

Kv10.1 structure [778] Structure of the eag domain–CNBHD complex [1724]


Structure of EAG1 ion Channel

Kv1.1 structure [778]

Structurally, Eag family are similar to other voltage-gated potassium channels, comprising of four identical α subunits each consisting of six membrane spanning domains (S1-S6) with cytoplasmic amino (N) and carboxy (C) termini. Pore region (P) is positioned between S5-S6. Chain of + arginine or lysine is separated by two hydrophobic residues within S4, this is where voltage is sensed. The N terminal consists of a Per-Arnt-Sim (PAS) domain, a hypoxia sensor leading to the activation of hypoxia inducible factor (HIF1), resulting in increased glycolysis and angiogenesis. The C terminus consists of a cyclic nucleotide binding domain (cNBD) and tetramerization-coil-coil domain with an Endoplasmic reticulum retention signal (RXR), which is involved in the tetramerization and functional expression. Also present on the C terminus are multiple signalling modules including putative nuclear export sequences (NES) and nuclear localization sequences (NLS) with binding sites for calmodulin (CaM), calcium/CaM-dependent protein kinaseII (CaMKII). These NES and NLS play an important role in perinuclear localization of these channels [1505]

N and C terminus

The ether-a-go-go family, named after the Drosophila prototype, is characterized by long N- and C-terminal intracellular tails [81]

Importance of PAS domain

However, for chimera I, which had the first 137 amino acids of heag2 replaced by the corresponding amino acids of heag1, the resulting construct was fast-activating, like heag1. This suggests that these N-terminal residues, which include the PAS domain, play a role in determining the differences in activation kinetics between the heag channels. Furthermore, for chimera II with residues 138–549 of the heag2 channel replaced by corresponding residues from heag1, the activation kinetics were again fast, like heag1. This indicates that the central, membrane- spanning region also plays a role in determining differ- ences in activation kinetics between the two channels [81]

Distributions


EAG Distribution in Neuron

A population of eag antennal sensory neurons appears to be insensitive to a subset of odorants. Is this mutant phenotype caused by a defect in a signal transduction component (Eag channel subunits)? In support of this, Eag K+ channels appear to be located on the outer dendrites of antennal neurons [1722]

EAG1 channels (kv10.1) are very noticeable in the perinuclear space of cells [1505]

Expressions


EAG expression in Human

In human, the Kv10s mRNA were detected by Northern blot in brain kidney lung and pancreas. In brain, they were expressed in cortex, hippocampus, caudate, putamen, amygdala and weakly in substantia nigra [675]

EAG expression in Rat

In rat, Kv10.1 products were detected in brain and weakly in testes. In situ hybridization in rat brain shows that Kv10.1 mRNAs are expressed in cortex, olfactory cortical structures, basal ganglia/striatal structures, hippocampus and in many nuclei of the amygdala complex. [675]

Also expressed in proximal regions of the extensions in human brains [1505]

Retina and Cochlea

Although eag subunits are specifically expressed in the adult rat brain, there are no reports about eag-mediated currents in normal neuro- nal tissue and the physiological role of eag in the central nervous system has still to be elucidated. However, there are indications that eag currents may be present in the retina as described below, and recently, eag1 mRNA has been found to be expressed in certain cells of the cochlea

Cancer

Increased expression of Eag-1 channels is found in several cancer types including breast cancer [768], [769].

Functionals


Cell Proliferation

These data together with the cell cycle-dependent expression of eag channels, suggest a direct involvement of eag channels in cell proliferation and prompt the possibility that eag channels participate in the transformation of normal cells into tumor cells. This idea was supported by the result that transfection of CHO cells with eag channels led to an increased proliferation rate [1721]


It has been shown that Eag-1 K+ channels, a member of the voltage-activated K+ channel superfamily, play a role in controlling the proliferation and transformation of epithelial cells [766], [767].


Along with BKCa, hEag1 channels not only regulate cell proliferation, but also participate in the adipogenic and osteogenic differentiations in human MSCs (human bone marrow-derived mesenchymal stem cells) [1512]

Channel trafficking

Silencing of Rabaptin-5 induces down-regulation of recycling of Kv10.1 channel in transfected cells and reduction of Kv10.1 current density in cells natively expressing Kv10.1, indicating a role of Rabaptin-5 in channel trafficking [1513]

Kv10.1 possesses oncogenic properties: ether-à-go-go type 1 (Eag1). [767]

Eag channels are expressed in fusing myoblasts and been posulated to have a role in their hyperpolarisation that preceeds their fusion [1507].

Photoreceptors

Eag channels are also involved in odour transduction and are encoded in seizure locus in Drosophila. In mammals, although Eag channels have been shown to be present in rat brain, their exact physiological function is not known, but in rat retina, they are known to be involved in the dark current-loop of photoreceptors [1505].

K/O mice

Because in mammals no physiological function has been reported so far, Kv10.1-deficient mice were experimented on to elucidate the functional role of Kv10.1 in the brain. However, successfully generated Kv10.1-deficient mice displayed no obvious differences from their littermate controls in the average life span, reproductive characteristics or development [1511]

Cancer

The Eag1 K(+) channel might be involved in the pathophysiological processes of prostate cancer, and is expected to be a valuable target for the diagnosis and treatment of prostate cancer [1514]

Tumour

KV10.1 potassium channels are implicated in a variety of cellular processes including cell proliferation and tumour progression. Their expression in over 70% of human tumours makes them an attractive diagnostic and therapeutic target [1509]

Kinetics


Schematic Drawing of EAG currents

Kv1.1 structure (D) Schematic drawing of an eag-mediated current. Upon a depolarization a slowly activating noninactivating outward cur- rent is elicited. Upon repolarization a small tail current occurs. (E) Schematic drawing of an erg-mediated K+ current elicited by a depolarization. At a negative holding potential, erg K channels are closed and deactivated. A strong depolarization elicits a small current transient followed by a small steady-state outward current because inactivation is faster than activation. Upon repolarization a large transient outward current occurs [778]

Intenral Na+ Concentration

Kv1.1 structure Currents recorded from a whole oocyte before (A) and after (B) the injection of 50 nl 2 M NaCl [1721]

Human EAG in X oocytes Kinetics

Kv1.1 structure Vpres of 10-s duration were applied in 15-mV increments to potentials ranging from −130 to +20 mV. After each prepulse, a test pulse was applied to +30 mV to assess channel availability. Under control conditions, hEAG1 currents activated with a Vpre ≥ −40 mV did not exhibit any time-dependent decay in magnitude. However, the peak current measured at the test pulse of +30 mV (Imax) decreased progressively as a function of Vpre, indicative of voltage-dependent inactivation. The extent of inactivation was small and only reduced Imax elicited after a prepulse to +20 mV by 5–10%. By comparison, the activation of hEAG1 currents developed over a more positive range of voltage, with a threshold near −55 mV, a V0.5 of −4.6 ± 0.7 mV, and z of 1.83 ± 0.06. Collectively, these findings indicate that hEAG1 channels inactivate from both closed and open states [1504]

High potassium content

Although the rate of C-type inactivation in Kv channels is slowed by high [K+]e, the rate of Y464A hEAG1 channel inactivation was unaffected by elevation of [K+]e from 2 to 20 mM, and slightly faster at 104 mM [1504]

Models


Markov Model

MarkovModel Kv10.1

Markov modelling demonstrated that simple 5- and 6-state models were inadequate and that a 10- or 12-state model was more appropriate for description of EAG1 channels [1504]


Hodgkin and Huxley Model for rEAG

HH Kv10.1 The continuous curves are the result of data fits according to a Hodgkin Huxley formalism ;data and fits were normalized to the fit result at +60 mV. [1723]

References


[765 : 21315112]
[766 : 18060344]
[767 : 16362499]
[768 : 17022810]
[769 : 17022811]
[648 : 12060745]
[1504 : 22930803]
[1505 : 21190577]
[1506 : 22495877]
[1507 : 9738473]
[1510 : 19805508]
[1511 : 23424202]
[1512 : 23881642]
[1513 : 22841712]
[1514 : 23700723]
[1516 : 24045971]
[675 : 15046870]
[81 : 14608450]
[1716 : 11211100]
[778 : 11426295]
[1717 : 9497369]
[1718 : 10559257]
[1719 : 9722534]
[1720 : 10416871]
[1721 : 9813096]
[1722 : 9671652]
[1723 : 9279806]
[1724 : 23975098]
[1509 : 24269539]

Credits


Editor : Admin.

Contributors : Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite : [Editor], [Contributors]. Accessed on [Date] Channelpedia , http://channelpedia.epfl.ch/ionchannels/33