CHRNA4

The CHRNA4 gene encodes the alpha-4 subunit of neuronal nicotinic acetylcholine receptors (nAChRs), a family of ligand-gated ion channels. These receptors, often termed α4β2-nAChRs when combined with beta-2 subunits, mediate synaptic signaling by binding acetylcholine or nicotine, triggering cation influx (Na⁺, K⁺, Ca²⁺) to depolarize neurons. Functionally, they modulate neurotransmitter release, synaptic plasticity, and cognitive processes. Key pathways include cholinergic signaling in the prefrontal cortex and mesolimbic reward circuits, impacting attention, memory, and addiction. CHRNA4-containing receptors are densely expressed in the thalamus, hippocampus, and dopaminergic pathways, linking them to both physiological neuromodulation and pathological states.
Mutations in CHRNA4 are associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), characterized by sleep-related seizures. Variants alter receptor desensitization kinetics, leading to hyperexcitability. Polymorphisms also correlate with nicotine dependence and Parkinson’s disease progression. Pharmacologically, α4β2-nAChR partial agonists like varenicline are approved for smoking cessation, while selective antagonists are explored for epilepsy. Recent trials target allosteric modulators to fine-tune receptor activity with reduced side effects. Emerging research investigates CHRNA4's role in neuroinflammation and its potential as a biomarker for cognitive decline in neurodegenerative disorders.