Top ▲

Kv12.2

Click here for help

Target not currently curated in GtoImmuPdb

Target id: 576

Nomenclature: Kv12.2

Family: Voltage-gated potassium channels (Kv)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1083 12q13.12 KCNH3 potassium voltage-gated channel subfamily H member 3
Mouse 6 1 1095 15 F1 Kcnh3 potassium voltage-gated channel, subfamily H (eag-related), member 3
Rat 6 1 1087 7q36 Kcnh3 potassium voltage-gated channel subfamily H member 3
Previous and Unofficial Names Click here for help
BEC1 | Elk2 | brain-specific eag-like channel 1 | ELK channel 2 | ether-a-go-go-like potassium channel 2 | potassium voltage-gated channel, subfamily H (eag-related), member 3 | potassium channel, voltage gated eag related subfamily H, member 3 | potassium voltage-gated channel
Database Links Click here for help
Alphafold Q9ULD8 (Hs), Q9WVJ0 (Mm), O89047 (Rn)
CATH/Gene3D 2.60.120.10
ChEMBL Target CHEMBL2363017 (Hs)
Ensembl Gene ENSG00000135519 (Hs), ENSMUSG00000037579 (Mm), ENSRNOG00000057315 (Rn)
Entrez Gene 23416 (Hs), 16512 (Mm), 27150 (Rn)
Human Protein Atlas ENSG00000135519 (Hs)
KEGG Gene hsa:23416 (Hs), mmu:16512 (Mm), rno:27150 (Rn)
OMIM 604527 (Hs)
Pharos Q9ULD8 (Hs)
RefSeq Nucleotide NM_012284 (Hs), NM_010601 (Mm), NM_017108 (Rn)
RefSeq Protein NP_036416 (Hs), NP_034731 (Mm), NP_058804 (Rn)
UniProtKB Q9ULD8 (Hs), Q9WVJ0 (Mm), O89047 (Rn)
Wikipedia KCNH3 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
KCNE1 2
KCNE3 2
Other Associated Proteins
Name References
HIV-1 gp120 4
Associated Protein Comments
siRNA silencing of KCNE1 and KCNE3 increased surface expression of Kv12.2 channels and currents in Xenopus oocytes in an additive fashion, and shifted the voltages for half-maximal activation to more hyperpolarized voltages. Over-expression of KCNE1 and/or KCNE3 suppressed Kv12.2 currents. Co-IP suggests the three proteins interact in mouse brain [2].

HIV-1 gp120 binds to the C-terminus (amino acids 973-1083) of Kv12.2 in vitro and in living cells. Overexpression of Kv12.2 inhibits HIV-1 particle release from 293T cells [4].
Ion Selectivity and Conductance Click here for help
Species:  Human
Macroscopic current rectification:  Ik
References:  1
Voltage Dependence Click here for help
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  24.9 - 3 CHO cells. Rat
Inactivation  - -
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -6.0 55.0 – 5.0 9 Xenopus laevis Oocytes Mouse
Inactivation  -2.5 5.0 – 8.0 9
Deactivation  - 39.0 9
Comments  (τ activation and inactivation at 50mV). Deactivation at -120mV

Steady-state activation and inactivation curves reveal substantial window current from -70mV to 60mV.

Inactivation arises from a C-type mechanism. [9]
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -6.0 – 24.0 - 1 CHO cells. Human
Inactivation  6.0 – 10.0 2.0 1
Deactivation  - 20.0 1
Comments  Deactivation at -120mV [1,3]. Removal of sugar chains causes a depolarizing shift in the steady-state activation without a significant reduction in current amplitude by a mechanism unrelated to negatively charged sialic acid residues in the sugar chains [7].

Download all structure-activity data for this target as a CSV file go icon to follow link

Activator Comments
External TEA+ slows inactivation and increases current amplitude with a half-maximal concentration (K1/2) of 97.09 ± 16.11 mM [9]
Gating inhibitors Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
CX4 Small molecule or natural product Mm Inhibition 5.0 pIC50 - -20.0 11
⤷ pIC50 5.0 [11]
Holding voltage: -20.0 mV
Description: 10 µM CX4 depolarizes voltage dependence of activation by ~+40 mV
Conditions: Voltage clamp of CHO cells heterologously expresing Kv12.2.
Channel Blockers
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
Cs+ Click here for species-specific activity table Hs Pore blocker 1.2 pKd - - 1
⤷ pKd 1.2 [1]
Channel Blocker Comments
Kv12.2 is resistant to block by external TEA, 4-AP, E-4031 [3,10]
Tissue Distribution Click here for help
Astrocytoma and neuroblastoma
Species:  Human
Technique:  RT-PCR
References:  1
Brain; expression concentrated in the telencephalic areas (cerebral cortex, amygdala, hippocampus, and striatum). Detected in the CA1-CA3 pyramidal cell layers, and dentate gyrus granule cell layers of the hippocampus. Specific signals are also found in neocortical neurons.
Species:  Human
Technique:  In situ hybridisation, Northern Blot
References:  5
Cerebellum, brainstem, hippocampus, upregulated in adult rat brain vs. embryonic rat brain
Species:  Rat
Technique:  In situ hybridisation
References:  3,8
Functional Assays Click here for help
Whole-cell patch clamp of heterologously expressed channel
Species:  Human
Tissue:  L929 cells
Response measured:  An outward current with a fast inactivation component.
References:  5
Voltage clamp to measure currents in heterologously expressed channels
Species:  Mouse
Tissue:  Xenopus laevis oocytes
Response measured:  A large, early inactivating component and a corresponding inward rectification. Inactivation occurs by a voltage-dependent, C-type inactivation mechanism.
References:  9
Whole-cell patch clamp of heterologously expressed channel
Species:  Rat
Tissue:  Chinese Hamster Ovary cells (CHO)
Response measured:  RELK2 channels gave rise to slowly activating K+ currents.
References:  3
Physiological Functions Click here for help
Evaluation of KO mice indicates the channel; is involved in setting resting membrane potential and influencing firing potential of hippocampal pyramidal neurons
Species:  Human
Tissue:  Neurons
References:  11
Physiological Consequences of Altering Gene Expression Click here for help
Kcnh3-/- mice did not exhibit seizures or motor dysfunction, and performed behavioural tasks related to spatial working memory (Y-maze), reference memory (water maze), and selective attention (water finding task) better than their wild-type litter mates. Overexpression in the forebrain caused impaired cognitive performance and reduced LTP.
Species:  Mouse
Tissue:  Forebrain
Technique:  Transgene expression vector constructed by inserting α-CaM-kinase II promoter into the pUC18 plasmid containing human Kcnh3 cDNA
References:  6
Hippocampal pyramidal neurons from Kcnh3-/- mice had depolarised resting membrane potentials, a reduced firing threshold and increased input resistance. Kcnh3-/- mice exhibited frequent interictal spiking, intermittent spontaneous nonconvulsive seizures lasting from 30-60s, and increased sensitivity to the chemoconvulsant pentylenetetrazol
Species:  Mouse
Tissue: 
Technique:  Conditional deletion of Kv12.2 with Cre recombinase (Kv12.2loxP)
References:  11
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnh3tm1Akmi Kcnh3tm1Akmi/Kcnh3tm1Akmi
involves: 129S4/SvJae * C57BL/6		 MGI:1341723  MP:0002206 abnormal CNS synaptic transmission PMID: 19923296 
Kcnh3tm1Akmi Kcnh3tm1Akmi/Kcnh3tm1Akmi
involves: 129S4/SvJae * C57BL/6		 MGI:1341723  MP:0002801 abnormal long term object recognition memory PMID: 19923296 
Kcnh3+|Kcnh3tm1Akmi Kcnh3tm1Akmi/Kcnh3+
involves: 129S4/SvJae * C57BL/6		 MGI:1341723  MP:0002801 abnormal long term object recognition memory PMID: 19923296 
Kcnh3tm1Akmi Kcnh3tm1Akmi/Kcnh3tm1Akmi
involves: 129S4/SvJae * C57BL/6		 MGI:1341723  MP:0002207 abnormal long term potentiation PMID: 19923296 
Kcnh3tm1.1Tije Kcnh3tm1.1Tije/Kcnh3tm1.1Tije
involves: C57BL/6		 MGI:1341723  MP:0003463 abnormal single cell response PMID: 20676103 
Kcnh3tm1.2Tije Kcnh3tm1.2Tije/Kcnh3tm1.2Tije
involves: C57BL/6		 MGI:1341723  MP:0003463 abnormal single cell response PMID: 20676103 
Kcnh3tm1Akmi Kcnh3tm1Akmi/Kcnh3tm1Akmi
involves: 129S4/SvJae * C57BL/6		 MGI:1341723  MP:0008414 abnormal spatial reference memory PMID: 19923296 
Kcnh3+|Kcnh3tm1Akmi Kcnh3tm1Akmi/Kcnh3+
involves: 129S4/SvJae * C57BL/6		 MGI:1341723  MP:0008414 abnormal spatial reference memory PMID: 19923296 
Kcnh3tm1Akmi Kcnh3tm1Akmi/Kcnh3tm1Akmi
involves: 129S4/SvJae * C57BL/6		 MGI:1341723  MP:0008428 abnormal spatial working memory PMID: 19923296 
Kcnh3tm1.2Tije Kcnh3tm1.2Tije/Kcnh3tm1.2Tije
involves: C57BL/6		 MGI:1341723  MP:0008840 abnormal spike wave discharge PMID: 20676103 
Kcnh3+|Kcnh3tm1.2Tije Kcnh3tm1.2Tije/Kcnh3+
involves: C57BL/6		 MGI:1341723  MP:0008840 abnormal spike wave discharge PMID: 20676103 
Kcnh3tm1.1Tije Kcnh3tm1.1Tije/Kcnh3tm1.1Tije
involves: C57BL/6		 MGI:1341723  MP:0003466 decreased single cell response threshold PMID: 20676103 
Kcnh3tm1.2Tije Kcnh3tm1.2Tije/Kcnh3tm1.2Tije
involves: C57BL/6		 MGI:1341723  MP:0003466 decreased single cell response threshold PMID: 20676103 
Kcnh3tm1.2Tije Kcnh3tm1.2Tije/Kcnh3tm1.2Tije
involves: C57BL/6		 MGI:1341723  MP:0002906 increased susceptibility to pharmacologically induced seizures PMID: 20676103 
Kcnh3tm1.2Tije Kcnh3tm1.2Tije/Kcnh3tm1.2Tije
involves: C57BL/6		 MGI:1341723  MP:0000948 nonconvulsive seizures PMID: 20676103 
General Comments
This channel has:
  • GFG (rather than the common GYG) potassium channel signature sequence
  • a PAS domain in the distal part of the cytosolic N-terminus
  • a cNBD domain in the proximal portion of the C-terminus

References

Show »

1. Becchetti A, De Fusco M, Crociani O, Cherubini A, Restano-Cassulini R, Lecchi M, Masi A, Arcangeli A, Casari G, Wanke E. (2002) The functional properties of the human ether-à-go-go-like (HELK2) K+ channel. Eur J Neurosci, 16 (3): 415-28. [PMID:12193184]

2. Clancy SM, Chen B, Bertaso F, Mamet J, Jegla T. (2009) 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, 4 (7): e6330. [PMID:19623261]

3. Engeland B, Neu A, Ludwig J, Roeper J, Pongs O. (1998) Cloning and functional expression of rat ether-à-go-go-like K+ channel genes. J Physiol (Lond.), 513 ( Pt 3): 647-54. [PMID:9824707]

4. Herrmann M, Ruprecht K, Sauter M, Martinez J, van Heteren P, Glas M, Best B, Meyerhans A, Roemer K, Mueller-Lantzsch N. (2010) Interaction of human immunodeficiency virus gp120 with the voltage-gated potassium channel BEC1. FEBS Lett, 584 (16): 3513-8. [PMID:20638388]

5. Miyake A, Mochizuki S, Yokoi H, Kohda M, Furuichi K. (1999) New ether-à-go-go K(+) channel family members localized in human telencephalon. J Biol Chem, 274 (35): 25018-25. [PMID:10455180]

6. Miyake A, Takahashi S, Nakamura Y, Inamura K, Matsumoto S, Mochizuki S, Katou M. (2009) Disruption of the ether-a-go-go K+ channel gene BEC1/KCNH3 enhances cognitive function. J Neurosci, 29 (46): 14637-45. [PMID:19923296]

7. Noma K, Kimura K, Minatohara K, Nakashima H, Nagao Y, Mizoguchi A, Fujiyoshi Y. (2009) Triple N-glycosylation in the long S5-P loop regulates the activation and trafficking of the Kv12.2 potassium channel. J Biol Chem, 284 (48): 33139-50. [PMID:19808681]

8. Saganich MJ, Machado E, Rudy B. (2001) Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. J Neurosci, 21 (13): 4609-24. [PMID:11425889]

9. Trudeau MC, Titus SA, Branchaw JL, Ganetzky B, Robertson GA. (1999) Functional analysis of a mouse brain Elk-type K+ channel. J Neurosci, 19 (8): 2906-18. [PMID:10191308]

10. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. (1995) HERG, a human inward rectifier in the voltage-gated potassium channel family. Science, 269 (5220): 92-5. [PMID:7604285]

11. Zhang X, Bertaso F, Yoo JW, Baumgärtel K, Clancy SM, Lee V, Cienfuegos C, Wilmot C, Avis J, Hunyh T et al.. (2010) Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci, 13 (9): 1056-8. [PMID:20676103]

Contributors

Show »

How to cite this page