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 kidney(1), alpha(2)-Adrenergic receptors are known to have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system(2-5); however, the individual roles of the three highly homologous alpha(2)-adrenergic-receptor subtypes (alpha(2A), alpha(2B), alpha(2C)) in this process are not known. We have now studied neurotransmitter release in mice in which the genes encoding the three alpha(z)-adrenergic-receptor subtypes were disrupted. Here we show that both the alpha(2A)- and alpha(2C)-subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. alpha(2A)-Adrenergic receptors inhibit transmitter release at high stimulation frequencies, whereas the a,c-subtype modulates neurotransmission at lower levels of nerve activity. Both low- and high-frequency regulation seem to be physiologically important, as mice lacking both alpha(2A)- and alpha(2C)-receptor subtypes have elevated plasma noradrenaline concentrations and develop cardiac hypertrophy with decreased left ventricular contractility by four months of age.