ADRA2C encodes an alpha-2 adrenergic receptor, a G protein-coupled receptor that binds catecholamines and activates the Gi/o protein pathway, suppressing adenylyl cyclase activity and inhibiting voltage-gated calcium channels. The receptor modulates neurotransmission at lower levels of noradrenergic nerve activity, with epinephrine showing highest potency among physiological agonists. ADRA2C is widely distributed across human tissues, including the central and peripheral nervous systems, where it mediates presynaptic feedback inhibition of norepinephrine release. ADRA2C has been genetically associated with multiple psychiatric and neurological conditions. A 2022 review identified ADRA2C polymorphisms among genes implicated in attention-deficit/hyperactivity disorder 1, and differential ADRA2C expression in the dorsolateral prefrontal cortex has been observed in schizophrenia, with antipsychotic treatment selectively upregulating ADRA2A but upregulating ADRA2C regardless of treatment status 2. Clinically, ADRA2C variants influence cardiovascular outcomes. A common deletion polymorphism (del322–325) was significantly enriched in patients with pheochromocytoma-induced catecholamine cardiomyopathy, with 95% negative predictive value for disease absence 3. ADRA2C polymorphisms have also been associated with differential response to the investigational beta-blocker bucindolol 4. Multiple approved agents targeting alpha-2 adrenergic signaling—including clonidine, brimonidine, and dexmedetomidine—are used for hypertension, glaucoma, and sedation, though current pharmacogenetic guidelines note insufficient evidence linking ADRA2C variants to therapeutic response across beta-blockers 5.