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Kv11.1

Family: Voltage-gated potassium channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Voltage Dependence
Activators
Gating Inhibitors
Pore Blockers
Tissue Distribution
Physiological Functions
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
Biologically Significant Variants
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1159 7q35-q36 KCNH2 potassium voltage-gated channel, subfamily H (eag-related), member 2
Mouse 6 1 1162 5 A3 Kcnh2 potassium voltage-gated channel, subfamily H (eag-related), member 2
Rat 6 1 1163 4q11 Kcnh2 potassium voltage-gated channel, subfamily H (eag-related), member 2
Previous and Unofficial Names
ether-à-go-go-related gene
HERG
erg1
hergb
LQT2
Kv11.1
ERG-1
RERG
eag-related protein 1
ether-a-go-go-related gene potassium channel 1
ether-a-go-go-related protein 1
potassium voltage-gated channel subfamily H member 2
r-ERG
voltage-gated potassium channel subunit Kv11.1
merg1a
M-erg
ether a go-go related
LQT
merg1b
AI326795
Database Links
ChEMBL Target
DrugBank Target
Ensembl
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProt
Wikipedia
Search for 3D structures on the PDB
Search by keyword: Voltage-gated potassium channels Kv11.1
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
KCNE1, minK 10,26,48
KCNE2, miRP1 1,15
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
GM130 33
KCR1 23,29
FKBP38 44
Hjd-2 44
Hop 44
Bag-2 44
Hsc 70 9
Hsp90 9
Associated Protein Comments
Controversy regarding MiRP1 interaction [47]
Ion Selectivity and Conductance
Species:  Human
Macroscopic current rectification:  Ik
References:  18,36-38,40,43
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -35.0 – -15.0 100.0 36,38,43 Xenopus laevis oocyte Human
Inactivation  - 4.0 – 20.0 18,37
Comments  τ activation at 20mV, τ inactivation at 40mV

Under voltage clamp, longer pulses drive V0.5 to more negative potentials. Removing the amino terminus causes negative shift that is no longer sensitive to pulse duration [38,43].

C-type inactivation mediates the strong rectifying properties characteristic of Kv11.1 / hERG channels [37,40].

The amino terminus slows deactivation and promotes C-type inactivation [46]. See [45] for detailed kinetic analysis of all hERG gating transitions, and see [35] for summary.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  - - HEK 293 cells. Human
Inactivation  -90.0 - 40
Associated subunits (Human)
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
NS1643 Hs 5.0 pEC50 - - 5,17
mallotoxin Hs 6.5 pIC50 - - 49
Activator Comments
NS1643: Slows inactivation and thus gives appearance of activating, does not directly affect activation [5,17]
Mallotoxin: speeds activation and slows deactivation [49]
Gating inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
BeKm-1 Hs 9.0 pKd - - 22
APETx-1 Hs 7.4 pKd - - 50
Gating Inhibitor Comments
ERG Toxin-1 / CnERG1 is a low nM binding scorpion toxin which inhibits by binding to outer mouth of the pore [19,30].
BeKm-1 is also a scorpion toxin which binds to the outer mouth of the pore [22]

APETx-1 is a sea anemone toxin whihc inhibits by binding to the S3b region of the voltage sensor [50]
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
E4031 Rn 7.0 pKd - - 39
Pore Blocker Comments
E-4031, dofetilide, terfenadine, and many other compounds, see [41] for review.
Drugs cross the cell membrane and enter hERG channels through open intracellular gate, where they then become trapped when channels close. Binding sites involve F656 and Y652 in the channel vestibule [24,27-28]. There remains controversy as to whether inhibition arises from a simple pore block mechanism or more complex processes also involving inactivation.
See [8,13] for studies involving Kv10 / EAG that provide intriguing insights into the role of inactivation in Kv11.1 / hERG drug binding.

Compounds have been identified that increase Kv11.1 function by enhancing ER export and may be useful as therapeutic agents in treating inherited or acquired LQTS [31]
Tissue Distribution
CNS - widely expressed, developing spinal cord
Species:  Rat
Technique:  In situ hybridisation
References:  11,16,34,39
Tissue Distribution Comments
Detected in the heart of all mammalian species studied to date, using electrophysiology, biochemistry and Northern blot. Also cancer cells of many types [3], and gut, pancreatic beta cells and many others.
Physiological Functions
hERG in smooth muscle contractility
Species:  Human
Tissue:  Jejenum
References:  7
Role in pancreatic beta cell secretion
Species:  Human
Tissue:  Pancreatic islet cells
References:  32
hERG channels regulate excitability in developing neurons
Species:  Mouse
Tissue:  Neural crest, spinal cord neurons
References:  4,11-12
In the human heart, Kv11.1 / hERG 1a and 1b subunits mediate the repolarizing cardiac current IKr. IKr peaks during late repolarization as a result of rebound from inactivation and slow deactivation. Loss of hERG function by mutations of the hERG gene (KCNH2) or by block by drugs intended largely for other therapeutic targets causes long QT syndrome (LQTS), which can lead to catastrophic arrhythmias and sudden death.
Species:  Human
Tissue:  Heart
References:  36,42,51
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0002128 abnormal blood circulation PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0001544 abnormal cardiovascular system physiology PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0000428 abnormal craniofacial morphology PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0000267 abnormal heart development PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0000266 abnormal heart morphology PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0000269 abnormal looping morphogenesis PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0004145 abnormal muscle electrophysiology PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0006126 abnormal outflow tract development PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0001698 decreased embryo size PMID: 18948620 
Kcnh2tm1Hjd Kcnh2tm1Hjd/Kcnh2tm1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0005333 decreased heart rate PMID: 12612061 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0006207 embryonic lethality during organogenesis PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0001636 irregular heartbeat PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0005312 pericardial effusion PMID: 18948620 
Kcnh2tm1.1Hjd Kcnh2tm1.1Hjd/Kcnh2tm1.1Hjd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1341722  MP:0006341 small first branchial arch PMID: 18948620 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Type 2 Long QT Syndrome
OMIM: 
Role: 
References:  2,6,14,36,42
Mutations not determined
Disease:  Acquired long QT syndrome
OMIM: 
Orphanet: 
Role: 
Side effects:  Torsades de Pointes arrhythmia
Therapeutic use:  hERG stable cell lines are used for counterscreening drugs in development as a safety test to prevent acquired LQTS
References:  41
Mutations not determined
Disease:  Short QT syndrome-1; SQT1
OMIM: 
Orphanet: 
References: 
Mutations not determined
Clinically-Relevant Mutations and Pathophysiology Comments
There are more than 200 mutations known for the KCNH2 gene, see Gene Connection for the Heart
Gene Expression and Pathophysiology
hERG sununits are aberrantly expressed (either over or mis-expressed) in many tumour types
Tissue or cell type:  Human primary cancers, tumour cell lines
Pathophysiology:  Putatively; Control of cell proliferation, regulation of tumour cell invasiveness (involving integrin family), control of tumour cell neoangiogensis (involving angiogenic factors).
Species:  Human
Technique:  -
References:  3
Biologically Significant Variants
hERG USO
Nucleotide accession:  NM_172056 
Protein accession:  NP_742053 
Amino acids:  888
Type:  Splice variant
Species:  Human
References:  23
hERG 1b variant; also referred to as isoform c. These subunits reduce rectification by increasing the rate of recovery from inactivation, thus yielding larger amplitude currents during ventricular action potential. Leads to somewhat reduced E-4031 sensitivity.
Nucleotide accession:  NM_172057 
Protein accession:  NP_742054 
Amino acids:  819
Type:  Splice variant
Species:  Human
References:  20-21,24-25
Isoform a
Nucleotide accession:  NM_000238 
Protein accession:  NP_000229 
Amino acids:  1159
Type:  Splice variant
Species:  Human
References: 
Biologically Significant Variant Comments
These are alternative transcripts rather than splice variants.

REFERENCES

To cite this database page, please use the following:

K. George Chandy, Stephan Grissmer, George A. Gutman, Michel Lazdunski, David Mckinnon, Luis A. Pardo, Gail A. Robertson, Bernardo Rudy, Michael C. Sanguinetti, Walter Stühmer, Xiaoliang Wang.
Voltage-gated potassium channels: Kv11.1. Last modified on 23/01/2012. Accessed on 20/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=572.


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