KCNH2 Protein — Potassium Voltage-Gated Channel

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KCNH2 Protein — Potassium Voltage-Gated Channel

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KCNH2 Protein — Potassium Voltage-Gated Channel

Introduction

Kcnh2 Protein — Potassium Voltage Gated Channel is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein"> [@smad]
| Field | Value | [@transcriptional]
|-------|-------| [@neuroinflammation]
| Protein Name | KCNH2 / HERG1 / Kv11.1 | [@astrocyte]
| Gene | KCNH2 |
| UniProt ID | Q14721 |
| PDB ID | 5VA1, 6EP6, 7CN3 |
| Molecular Weight | ~127 kDa (native tetramer) |
| Subcellular Localization | Plasma membrane, Cytoplasm |
| Protein Family | Voltage-gated potassium channel (Kv11.1, EAG family) |
| Structure | Tetramer of 6TM subunits |
</div>

Overview

KCNH2 (also known as HERG1, Kv11.1, or EAG1) is the α-subunit of the cardiac rapid delayed rectifier potassium channel (I_Kr). This voltage-gated potassium channel is critical for cardiac repolarization and is also expressed in [neurons](/entities/neurons) where it regulates excitability. The channel has unique biophysical properties including slow deactivation and inactivation, and is a major drug target due to its role in cardiac safety.

Structure

Channel Architecture

The KCNH2 channel is a tetrameric protein, with each subunit containing:

S1-S4: Voltage sensor domain
S5-S6: Pore domain with selectivity filter
N-terminus: PAS domain (Per-Arnt-Sim) involved in gating
C-terminus: Cyclic nucleotide-binding domain (CNBD)

...

KCNH2 Protein — Potassium Voltage-Gated Channel

Introduction

Kcnh2 Protein — Potassium Voltage Gated Channel is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein"> [@smad]
| Field | Value | [@transcriptional]
|-------|-------| [@neuroinflammation]
| Protein Name | KCNH2 / HERG1 / Kv11.1 | [@astrocyte]
| Gene | KCNH2 |
| UniProt ID | Q14721 |
| PDB ID | 5VA1, 6EP6, 7CN3 |
| Molecular Weight | ~127 kDa (native tetramer) |
| Subcellular Localization | Plasma membrane, Cytoplasm |
| Protein Family | Voltage-gated potassium channel (Kv11.1, EAG family) |
| Structure | Tetramer of 6TM subunits |
</div>

Overview

KCNH2 (also known as HERG1, Kv11.1, or EAG1) is the α-subunit of the cardiac rapid delayed rectifier potassium channel (I_Kr). This voltage-gated potassium channel is critical for cardiac repolarization and is also expressed in [neurons](/entities/neurons) where it regulates excitability. The channel has unique biophysical properties including slow deactivation and inactivation, and is a major drug target due to its role in cardiac safety.

Structure

Channel Architecture

The KCNH2 channel is a tetrameric protein, with each subunit containing:

S1-S4: Voltage sensor domain
S5-S6: Pore domain with selectivity filter
N-terminus: PAS domain (Per-Arnt-Sim) involved in gating
C-terminus: Cyclic nucleotide-binding domain (CNBD)

Key Structural Features

| Domain | Residues | Function |
|--------|----------|----------|
| PAS Domain | 1-135 | Gating regulation |
| S1-S4 VSD | 181-420 | Voltage sensing |
| S5-S6 Pore | 421-644 | Ion conduction |
| CNBD | 655-872 | Cyclic nucleotide binding |

Structure-Specific Insights

Crystal structures reveal the architecture of the voltage sensor and pore domains
The selectivity filter has the characteristic GYG sequence
The PAS domain interacts with the channel core to modulate gating

Normal Function

Cardiac Function

In cardiac myocytes, KCNH2 conducts the rapid delayed rectifier potassium current (I_Kr), which is essential for:

Phase 3 repolarization of the action potential
Setting action potential duration
Preventing early afterdepolarizations

Neuronal Function

In neurons, KCNH2 channels:

Contribute to action potential repolarization
Regulate spike frequency
Modulate dendritic integration
Influence neurotransmitter release

Role in Disease

Cardiovascular Disease

Long QT Syndrome Type 2 (LQT2)

Most common pathogenic KCNH2 mutations cause loss-of-function
Leads to prolonged QT interval on ECG
Risk of torsades de pointes and sudden cardiac death
Triggers include auditory stimuli, stress, and certain medications

Short QT Syndrome Type 1

Gain-of-function KCNH2 mutations
Excessively short QT interval
High risk of atrial fibrillation and ventricular fibrillation

Neurodegenerative Disease

Alzheimer's Disease

[Aβ](/proteins/amyloid-beta) peptides reduce KCNH2 current density
Channel dysfunction contributes to neuronal hyperexcitability
Altered expression in AD brain regions
HERG modulators may have therapeutic potential

Parkinson's Disease

Expressed in dopaminergic neurons
May affect neuronal survival
Interactions with PD-associated proteins

Therapeutic Targeting

Approved Drugs Targeting KCNH2

| Drug | Type | Indication | Cardiac Risk |
|------|------|------------|-------------|
| Dofetilide | Blocker | Atrial fibrillation | Yes (QT prolongation) |
| Ibutilide | Blocker | Arrhythmia | Yes |
| Dronedarone | Blocker | Atrial fibrillation | Yes |
| Amiodarone | Blocker | Various arrhythmias | Yes |

Drug Safety Considerations

Many drugs block KCNH2, causing QT prolongation
Cardiac toxicity is a major concern in drug development
Torsades de pointes is a potential adverse effect

Therapeutic Strategies for Neurodegeneration

Channel Activators: Could improve neuronal function in AD
Selective Modulators: Avoid cardiac side effects
Gene Therapy: Potential for precise targeting
Protein-Protein Interaction Inhibitors: Target toxic interactions

Key Publications

PMID: 7546119(https://pubmed.ncbi.nlm.nih.gov/7546119/) - HERG encodes the IKr potassium channel (1995)

PMID: 8794898(https://pubmed.ncbi.nlm.nih.gov/8794898/) - KCNH2 mutations causing Long QT syndrome (1996)

PMID: 15671032(https://pubmed.ncbi.nlm.nih.gov/15671032/) - Amyloid-beta effects on neuronal ion channels (2005)

PMID: 20430974(https://pubmed.ncbi.nlm.nih.gov/20430974/) - HERG channel as therapeutic target in AD (2010)

PMID: 28847562(https://pubmed.ncbi.nlm.nih.gov/28847562/) - Cryo-EM structure of HERG channel (2017)

External Links

[UniProt: Q14721](https://www.uniprot.org/uniprot/Q14721)
[PDB: 5VA1](https://www.rcsb.org/structure/5VA1)
[IUPHAR: KCNH2](https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=575)

Background

The study of Kcnh2 Protein — Potassium Voltage Gated Channel has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[NPAS Gene Family](/npas-gene-family)
[Circadian Clock Genes](/circadian-clock-genes)
[BMAL1/CLOCK Complex](/b## External Links
[NPAS2 Gene - NCBI](https://www.ncbi.nlm.nih.gov/gene/10826)

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Related Entities

KCNH2PROTEIN

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

85%

Debates

0

Incoming

17

Outgoing

22

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

KCNH2 Protein — Potassium Voltage-Gated Channel

KCNH2 Protein — Potassium Voltage-Gated Channel

Introduction

Overview

Structure

Channel Architecture

KCNH2 Protein — Potassium Voltage-Gated Channel

Introduction

Overview

Structure

Channel Architecture

Key Structural Features

Structure-Specific Insights

Normal Function

Cardiac Function

Neuronal Function

Role in Disease

Cardiovascular Disease

Long QT Syndrome Type 2 (LQT2)

Short QT Syndrome Type 1

Neurodegenerative Disease

Alzheimer's Disease

Parkinson's Disease

Therapeutic Targeting

Approved Drugs Targeting KCNH2

Drug Safety Considerations

Therapeutic Strategies for Neurodegeneration

Key Publications

See Also

External Links

Background

References

💬 Discussion