The endogenous catecholamines epinephrine and norepinephrine have profound effects on smooth muscle activity, cardiac function, carbohydrate and fat metabolism, hormone secretion, neurotransmitter release, and central nervous system actions. These activities are mediated by GPCRs belonging to two subfamilies, the alpha- and beta-adrenoceptors. The alpha2 adrenergic receptor subfamily members, consisting of alpha2A, alpha2B, and alpha2C, couple primarily to Gi to inhibit cAMP production, and play an important role in regulation of cardiovascular and CNS function. The alpha2A receptor at presynaptic sites has an inhibitory effect on catecholamine release from sympathetic nerve endings. Experiments with alpha2A-selective agonists and mice lacking alpha2A demonstrate that activation of alpha2A results in hypotension, sedation, analgesia, and hypothermia.