Alpha-2-adrenergic receptors, including ADRA2A, are members of the G protein-coupled receptor superfamily. They include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. Studies in mouse revealed that both ADRA2A and ADRA2C subtypes were required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. The ADRA2A subtype inhibited transmitter release at high stimulation frequencies, whereas the ADRA2C subtype modulated neurotransmission at lower levels of nerve activity.