HCN4: Hyperpolarization-activated Cyclic Nucleotide-gated Channel 4 [Neurosurgery Wiki]

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====== 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 **I<sub>f</sub> 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 I<sub>f</sub> 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