HCN4: Hyperpolarization-activated Cyclic Nucleotide-gated Channel 4
Gene: HCN4
Chromosomal location: 15q24.1
Channel type: Non-selective cation channel
Ion conductance: Na⁺ / K⁺
Activation: Hyperpolarization and intracellular cAMP binding
🧬 Function
- Generates the If current (“funny current”) in the sinoatrial (SA) node
- Essential for spontaneous diastolic depolarization and cardiac pacemaker activity
- In the CNS, modulates:
- Resting membrane potential
- Synaptic responsiveness
- Rhythmic and oscillatory neuronal firing
- Sensitive to intracellular cAMP (↑ sympathetic tone → ↑ firing rate)
⚠️ Pathophysiology
| Condition | Description |
|---|---|
| Familial sinus bradycardia | Loss-of-function mutations → persistently slow heart rate |
| Sick sinus syndrome | SA node dysfunction causing pauses or arrest |
| Atrial fibrillation (rare cases) | Linked to altered pacemaker mechanisms |
| CNS disorders (investigational) | Involvement in epilepsy, depression, autism (under study) |
🧪 Structure
- Six transmembrane domains (S1–S6)
- P-loop between S5–S6 forms the pore
- Intracellular cyclic nucleotide-binding domain (CNBD) at the C-terminus
- Forms tetrameric structure for channel function
💊 Clinical Relevance
- Ivabradine: Selective If current blocker used in:
- Chronic heart failure
- Stable angina (reduces HR without negative inotropy)
- Genetic screening for unexplained bradycardia or syncope
- Potential target for neuromodulation strategies in CNS diseases