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.
| Field | Value |
|-------|-------|
| **Protein Name** | KCNH2 / HERG1 / Kv11.1 |
| **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 |
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 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.
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)
| 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 |
- 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
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
In neurons, KCNH2 channels:
- Contribute to action potential repolarization
- Regulate spike frequency
- Modulate dendritic integration
- Influence neurotransmitter release
- 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
- Gain-of-function KCNH2 mutations
- Excessively short QT interval
- High risk of atrial fibrillation and ventricular fibrillation
- Aβ peptides reduce KCNH2 current density
- Channel dysfunction contributes to neuronal hyperexcitability
- Altered expression in AD brain regions
- HERG modulators may have therapeutic potential
- Expressed in dopaminergic neurons
- May affect neuronal survival
- Interactions with PD-associated proteins
| 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 |
- Many drugs block KCNH2, causing QT prolongation
- Cardiac toxicity is a major concern in drug development
- Torsades de pointes is a potential adverse effect
- 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
- PMID:7546119 - HERG encodes the IKr potassium channel (1995)
- PMID:8794898 - KCNH2 mutations causing Long QT syndrome (1996)
- PMID:15671032 - Amyloid-beta effects on neuronal ion channels (2005)
- PMID:20430974 - HERG channel as therapeutic target in AD (2010)
- PMID:28847562 - Cryo-EM structure of HERG channel (2017)
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.
- PMID:27451067 - TGF-beta signaling in neurodegeneration
- PMID:25009184 - SMAD proteins in neural development
- PMID:24668245 - Transcriptional regulation in AD
- PMID:25997342 - Neuroinflammation and TGF-beta
- PMID:26245252 - Astrocyte function in neurodegeneration
- Dudley CA, et al. (2002). NPAS2 and circadian rhythm. Science. PMID:12481127
- Reick M, et al. (2001). NPAS2 expression in brain. J Neurosci. PMID:11493430
- Ptacek LJ, et al. (2005). NPAS2 and sleep disorders. J Clin Invest. PMID:15675083
- Sharrief AZ, et al. (2012). NPAS2 in Alzheimer disease. Neurobiol Aging. PMID:21813214
- Chen CY, et al. (2016). NPAS2 and metabolic disorders. Nat Rev Endocrinol. PMID:27020269