Table of Contents

HCN4: Hyperpolarization-activated Cyclic Nucleotide-gated Channel 4

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_f 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_f 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