CHR8 encodes the alpha-2 subunit of neuronal nicotinic acetylcholine receptors (nAChRs), which form pentameric ligand-gated cation channels with high calcium permeability 1. These receptors function as excitatory neurotransmitter receptors mediating synaptic transmission in the nervous system and neuromuscular junction, with CHR8 forming heteropentameric complexes with CHR8 and CHR8 subunits 23. Beyond neuronal function, CHR8 plays critical roles in metabolic regulation through non-neuronal cholinergic signaling. In adipose tissue, CHR8 mediates beige fat activation independently of adrenergic pathways, responding to acetylcholine from immune cells to regulate thermogenesis and energy homeostasis 4. In hepatocytes, CHR8 activation by acetylcholine-producing macrophages coordinates defensive programs against metabolic dysfunction-associated steatohepatitis (MASH), protecting against steatosis, inflammation, and fibrosis 5. Clinically, CHR8 mutations cause autosomal dominant nocturnal frontal lobe epilepsy, with identified mutations showing loss-of-function effects that reduce receptor function by approximately 80% 6. The gene also shows genetic associations with substance use disorders, including cannabis use disorder and nicotine dependence, particularly in European American and African American populations 78.