Sodium Channel Protein Nav1.1 is encoded by the SCN1A gene on chromosome 2q24. It is a voltage-gated sodium channel (NaV1.1) primarily expressed in fast-spiking inhibitory interneurons. While classically associated with epilepsy and Dravet syndrome, Nav1.1 dysfunction is increasingly recognized in neurodegenerative conditions including Alzheimer's disease and ALS.
- Length: 2008 amino acids
- Molecular Weight: ~226 kDa
- Domains:
- Domain I (1-426): Voltage sensor and pore S1-S4
- Domain II (427-853): Voltage sensor and pore S1-S4
- Domain III (854-1245): Voltage sensor and pore S1-S4
- Domain IV (1246-1622): Voltage sensor and pore S1-S4
- C-terminal domain (1623-2008): Interaction domains and localization signals
| Region |
AA Positions |
Function |
| Voltage sensor |
S4 segments |
Depolarization detection |
| Pore loop |
Between DIII-DIV |
Na+ selectivity filter |
| IFM motif |
DIII-DIV linker |
Fast inactivation gate |
- Rapid Na+ influx during depolarization
- Critical for action potential initiation in neurons
- Essential for high-frequency firing in inhibitory interneurons
- Controls neuronal excitability and network synchronization
- Predominantly expressed in GABAergic interneurons
- Also present in pyramidal neurons (lower density)
- Subcellular localization: axon initial segment, nodes of Ranvier
-
Neuronal Hyperexcitability
- Aβ oligomers downregulate Nav1.1 expression
- Loss of inhibitory interneuron function
- Contributes to network hyperactivation and seizures
-
Excitotoxicity
- Impaired Na+ homeostasis increases glutamate toxicity
- Dysregulated Ca2+ entry through reverse NCX operation
- Exacerbates amyloid-induced neuronal death
- Reduced Nav1.1 in motor cortex interneurons
- Loss of inhibitory control contributes to hyperexcitability
- Associated with cortical disinhibition in ALS patients
- Shared mechanisms between epileptogenesis and neurodegeneration
- Sodium channel dysfunction as common pathway
| Agent |
Status |
Mechanism |
| Carbamazepine |
Approved |
Na+ channel blocker |
| Lacosamide |
Approved |
Enhanced slow inactivation |
| Fenfluramine |
Approved (Dravet) |
Multi-target antidepressant |
- Gene therapy for loss-of-function mutations
- Antisense oligonucleotides targeting toxic transcripts
- Small molecules promoting Nav1.1 trafficking