K<SUB>v</SUB>12.2 | Voltage-gated potassium channels | IUPHAR/BPS Guide to PHARMACOLOGY

Kv12.2

Target id: 576

Nomenclature: Kv12.2

Family: Voltage-gated potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for Kv12.2 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1083 12q13 KCNH3 potassium voltage-gated channel subfamily H member 3
Mouse 6 1 1095 15 F3 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
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
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
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
Species:  Human
Macroscopic current rectification:  Ik
References:  1
Voltage Dependence
  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

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
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
CX4 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 Affinity Units Concentration range (M) Holding voltage (mV) Reference
Cs+ 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
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
Astrocytoma and neuroblastoma
Species:  Human
Technique:  RT-PCR
References:  1
Cerebellum, brainstem, hippocampus, upregulated in adult rat brain vs. embryonic rat brain
Species:  Rat
Technique:  In situ hybridisation
References:  3,8
Functional Assays
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
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
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 Mouse data from MGI

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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

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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

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How to cite this page

Michael C. Sanguinetti, K. George Chandy, Stephan Grissmer, George A. Gutman, Michel Lazdunski, David Mckinnon, Luis A. Pardo, Gail A. Robertson, Bernardo Rudy, Walter Stühmer, Xiaoliang Wang.
Voltage-gated potassium channels: Kv12.2. Last modified on 20/07/2015. Accessed on 17/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=576.