ADRA2A

ADRA2A is the gene that encodes the alpha-2A adrenergic receptor, a member of the G protein-coupled receptor (GPCR) family that binds catecholamines such as norepinephrine and epinephrine, with a preference for norepinephrine in several tissues. The receptor is part of the alpha-2 adrenergic receptor subfamily and functions as a modulator of sympathetic signaling.

Mechanistically, the alpha-2A receptor couples to inhibitory G proteins (Gi/o). Upon activation, it inhibits adenylate cyclase, reducing cAMP levels, and modulates ion channels to decrease calcium influx and often increase potassium conductance. This signaling lowers neurotransmitter release and neuronal excitability. The receptor also acts presynaptically as an autoreceptor to limit further norepinephrine release, and it can participate in heteroreceptor signaling in various neural and peripheral circuits.

Expression and roles are broad but tissue-specific. In the central nervous system, the alpha-2A receptor is abundant in areas involved in arousal and stress responses and contributes to analgesia and sedation. Peripherally, it is found in platelets, vascular smooth muscle, pancreatic islets, and adipose tissue, where it influences vascular tone, insulin secretion, and lipolysis. Pharmacologically, selective alpha-2A agonists such as guanfacine and dexmedetomidine are used clinically for hypertension, ADHD, and sedation, while antagonists like yohimbine increase norepinephrine release.

Genetic variation in ADRA2A can affect receptor expression and drug response, with research exploring associations to ADHD, metabolic traits, and blood pressure regulation. Despite these associations, ADRA2A variations are not currently tied to a single disease.