Two functionally distinct α2-adrenergic receptors regulate sympathetic neurotransmission

The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney1. α2-Adrenergic receptors are known to have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system2,3,4,5; however, the individual roles of the three highly homologous α2-adrenergic-receptor subtypes (α2A, α2B, α2C) in this process are not known. We have now studied neurotransmitter release in mice in which the genes encoding the three α2-adrenergic-receptor subtypes were disrupted. Here we show that both the α2A- and α2C-subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. α2A-Adrenergic receptors inhibit transmitter release at high stimulation frequencies, whereas the α2C-subtype modulates neurotransmission at lower levels of nerve activity. Both low- and high-frequency regulation seem to be physiologically important, as mice lacking both α2A- and α2C-receptor subtypes have elevated plasma noradrenaline concentrations and develop cardiac hypertrophy with decreased left ventricular contractility by four months of age.