Kv12.2

Description: potassium voltage-gated channel, subfamily H (eag-related), member 3
Gene: Kcnh3
Alias: Kv12.2

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Introduction

Kv12.2, encoded by the gene KCNH3, is potassium voltage-gated channel subfamily H member 3 [606], [810]. It is also known as BEC1; ELK2; Kv12.2; KIAA1282.

Experimental data

Rat Kv12.2 gene in CHO host cells datasheet
Click for details 15 °C show 47 cells	Click for details 25 °C show 59 cells	Click for details 35 °C show 65 cells

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Gene

Kv12.2, also known as ether-a-go-go-like 2 (Elk2) or KCNH3, belongs to the ether-a-go-go (EAG) family, which comprises the ether-a-go-go (Eag, Kv10.x), ether-a-go-go-related gene (Erg, Kv11.x), and ether-a-go-go like (Elk, Kv12.x) subfamilies [812], [778].

Species	NCBI gene ID	Chromosome	Position
Human	23416	12	19307
Mouse	16512	15	18303
Rat	27150	7	18266

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_012284.3	4023
Mouse	NM_010601.4	3967
Rat	NM_017108.1	3715

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Protein Isoforms

Unlike Kv5.x, Kv6.x, Kv8.x, and Kv9.x, which function as modifiers for other Kv channels [606], Kv12.2 can produce a functional channel on its own when heterologously expressed [809], [808], [813]. (From [802])

Species	Uniprot ID	Length (aa)
Human	Q9ULD8	1083
Mouse	Q9WVJ0	1095
Rat	O89047	1087

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_012284.3

4023

NP_036416.1

1083

transcript variant 1

isoform 1

NM_001314030.2

4019

NP_001300959.1

1023

transcript variant 2

isoform 2

Predicted

XM_011538085.3

4056

XP_011536387.1

1094

transcript variant X1

isoform X1

XM_047428613.1

2162

XP_047284569.1

560

transcript variant X2

isoform X2

XM_054371580.1

4056

XP_054227555.1

1094

transcript variant X1

isoform X1

XM_054371581.1

2162

XP_054227556.1

560

transcript variant X2

isoform X2

Known

NM_010601.4

3967

NP_034731.3

1095

Predicted

XM_006520483.5

4063

XP_006520546.1

1101

transcript variant X1

isoform X1

XM_036159170.1

3712

XP_036015063.1

1041

transcript variant X3

isoform X2

XM_036159171.1

3692

XP_036015064.1

1035

transcript variant X5

isoform X3

XM_030248344.2

3671

XP_030104204.1

1035

transcript variant X6

isoform X3

XM_006520484.4

3614

XP_006520547.1

1041

transcript variant X2

isoform X2

XM_030248343.2

3596

XP_030104203.1

1035

transcript variant X4

isoform X3

Known

NM_017108.1

3715

NP_058804.1

1087

Predicted

XM_039078512.1

3269

XP_038934440.1

837

transcript variant X3

isoform X2

XM_039078511.1

3786

XP_038934439.1

1027

transcript variant X1

isoform X1

XM_017594683.2

4602

XP_017450172.1

1027

transcript variant X2

isoform X1

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Post-Translational Modifications

Glycosylation in CHO Cells

N-glycosylation effects the function of Kv12.2, in as much as that removal of sugar chains causes a depolarizing shift in the steady-state activation without a significant reduction in current amplitude. Unlike the previously reported shift for Shaker-type Kv channels, this shift does not appear to be due to negatively charged sialic acid residues in the sugar chains. Kv12.2 is N-glycosylated in Chinese hamster ovary (CHO) cells and in cultured neurons as well as in the mouse brain. Only glycosylated Kv12.2 channels show proper voltage dependence and are utilized in vivo. [802]

PTM

Position

Type

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Structure

Visual Representation of Kv12.2 Structure
Methodology for visual representation of structure available here

There is a light oxygen voltage (LOV) and cyclic nucleotide binding (CNB) domain in the N and C terminus, respectively. [606]

Kv12.2 features the longest S5-P loop among all known mammalian Kv channels with the most N-linked glycosylation sites (three sites). [802]

Kv12.2 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	8831.41	source
Mouse	7533.45	source
Rat	9364.01	source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

Rat Kv12.2 channels very similar to HERG

RELK2 channels gave rise to slowly activating K+ currents. At more positive potentials, the evoked currents inactivated rapidly. Recovery from inactivation at negative potentials was reminiscent of that seen for HERG channels [809]

Mouse Kv12.2 in CHO cells display Current with EGFP

Here we present the evidence that Kv12.2 channels are expressed and N-glycosylated in the mouse brain and that N-glycosylation is essential for proper function of EGFP-Kv12.2 expressed in Chinese hamster ovary (CHO) cells. Furthermore, by a systematic mutational analysis of the three glycosylation sites of Kv12.2, our study provides insight into how glycosylation regulates the trafficking of Kv channels. To improve the reproducibility of our measurements, we fused EGFP to the N terminus of Kv12.2. When cells were transfected with EGFP-Kv12.2, almost all EGFP-positive cells showed voltage-dependent transient outward currents and characteristic tail currents, which were absent in mock-transfected cells. The currents were similar to those of untagged Kv12.2 channels which were previously reported. We, therefore, concluded that EGFP-Kv12.2 could be used for further characterization of the channel [802] For other scenarios in CHO cells EGFP was also used [809]

pH sensitivity of Kv12.1,Kv12.2 and Kv12.3

Whole cell patch clamp recordings made on HEK293 cells transfected with Elk channels hKv12.1, hKv12.2, and hKv12.3 demonstrated that external acidification inhibits their activation. High sensitivity to physiological changes in pH may be a general feature of the EAG superfamily of K+ channels as it was also observed for Kv10.1 and Kv11.1.[1832]

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Expression and Distribution

Kv12.2 was found in infant brain, lung (small cell carcinoma), eye (retinoblastoma), sciatic nerve, cortex, amygdala, hippocampus (mainly in CA1 and CA3 pyramidal cell body layers and in the granule cell layers of the dentate gyrus); in the striatal regions, including the putamen and caudate nucleus, lymphocytes, leukemias, and NG108-15 cell line. [327], [793], [810], [809], [811]. (Summary from [606])

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Function

Astrocytoma

ELK2 channels are very effective at dampening the neuronal excitability, but less so at producing adaptation of action potential firing frequency. In addition, we suggest experimental ways to recognize HELK2 currents in vivo and raise the issue of the possible function of these channels in astrocytoma [813]

Hyppocampal Hyperexcitability and Epilepsy

Human Kv12.2 may be implicated in epilepsy [814]. We show here that the voltage-gated K+ channel Kv12.2 is a potent regulator of excitability in hippocampal pyramidal neurons. Genetic deletion and pharmacologic block of Kv12.2 significantly reduced firing threshold in these neurons. Kv12.2−/− mice displayed signs of persistent neuronal hyperexcitability including frequent interictal spiking, spontaneous seizures and increased sensitivity to the chemoconvulsant pentylenetetrazol [803]

Cognitive Function

Disruption of the Ether-à-go-go K+ Channel Gene Kv12.2/KCNH3 Enhances Cognitive Function [1786]

Transcription of KCNH3

The transcription of KCNH3 the gene coding for Kv12.2 may be activated by the transcription factor FOXG1 in mature neurons of the CNS suggesting a possible link to the FOXG1 syndrome pathology [2086]

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Interaction

KCNE1 and KCNE3

KCNE1 and KCNE3 beta-subunits regulate membrane surface expression of kv12.2 channels in vitro and form tripartite complex in vivo [801]

E4031

RELK1 and RELK2 currents were not blocked by 10 μm E4031 (n = 5), which blocks HERG channels, nor by 10 μm linopirdine (n = 5), which blocks M-channels [809]

References

327

Saganich MJ et al. Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain.
J. Neurosci., 2001 Jul 1 , 21 (4609-24).

606

Gutman GA et al. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels.
Pharmacol. Rev., 2005 Dec , 57 (473-508).

778

Bauer CK et al. Physiology of EAG K+ channels.
J. Membr. Biol., 2001 Jul 1 , 182 (1-15).

793

Meves H et al. Separation of M-like current and ERG current in NG108-15 cells.
Br. J. Pharmacol., 1999 Jul , 127 (1213-23).

801

Clancy SM et al. KCNE1 and KCNE3 beta-subunits regulate membrane surface expression of Kv12.2 K(+) channels in vitro and form a tripartite complex in vivo.
PLoS ONE, 2009 , 4 (e6330).

802

Noma K et al. Triple N-glycosylation in the long S5-P loop regulates the activation and trafficking of the Kv12.2 potassium channel.
J. Biol. Chem., 2009 Nov 27 , 284 (33139-50).

803

Zhang X et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy.
Nat. Neurosci., 2010 Sep , 13 (1056-8).

808

Zou A et al. Distribution and functional properties of human KCNH8 (Elk1) potassium channels.
Am. J. Physiol., Cell Physiol., 2003 Dec , 285 (C1356-66).

809

Engeland B et al. Cloning and functional expression of rat ether-à-go-go-like K+ channel genes.
J. Physiol. (Lond.), 1998 Dec 15 , 513 ( Pt 3) (647-54).

810

Miyake A et al. New ether-à-go-go K(+) channel family members localized in human telencephalon.
J. Biol. Chem., 1999 Aug 27 , 274 (25018-25).

811

Smith GA et al. Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells.
J. Biol. Chem., 2002 May 24 , 277 (18528-34).

812

Ganetzky B et al. The eag family of K+ channels in Drosophila and mammals.
Ann. N. Y. Acad. Sci., 1999 Apr 30 , 868 (356-69).

813

Becchetti A et al. The functional properties of the human ether-à-go-go-like (HELK2) K+ channel.
Eur. J. Neurosci., 2002 Aug , 16 (415-28).

814

Grosso S et al. Epilepsy and electroencephalographic findings in pericentric inversion of chromosome 12.
J. Child Neurol., 2004 Aug , 19 (604-8).

1786

Miyake A et al. Disruption of the ether-a-go-go K+ channel gene BEC1/KCNH3 enhances cognitive function.
J. Neurosci., 2009 Nov 18 , 29 (14637-45).

1832

Kazmierczak M et al. External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor.
J. Gen. Physiol., 2013 Jun , 141 (721-35).

2086

Vezzali R et al. The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activates Kcnh3 expression in mature neurons.
Oncotarget, 2016 May 21 , ().

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Credits

Contributors: Rajnish Ranjan, Katherine Johnston

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/39/ , accessed on 2024 Dec 21

Add section

Kv12.2

Introduction

Experimental data

Rat Kv12.2 gene in CHO host cells datasheet

15 °C

25 °C

35 °C

Gene

Transcript

Protein Isoforms

Isoforms

Post-Translational Modifications

Glycosylation in CHO Cells

Structure

Kv12.2 predicted AlphaFold size

Kinetics

Rat Kv12.2 channels very similar to HERG

Mouse Kv12.2 in CHO cells display Current with EGFP

pH sensitivity of Kv12.1,Kv12.2 and Kv12.3

Expression and Distribution

Function

Astrocytoma

Hyppocampal Hyperexcitability and Epilepsy

Cognitive Function

Transcription of KCNH3

Interaction

KCNE1 and KCNE3

E4031

References

Credits