Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission

Nature. 1999 Nov 11;402(6758):181-4. doi: 10.1038/46040.


The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney. Alpha2-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; however, the individual roles of the three highly homologous alpha2-adrenergic-receptor subtypes (alpha2A, alpha2B, alpha2C) in this process are not known. We have now studied neurotransmitter release in mice in which the genes encoding the three alpha2-adrenergic-receptor subtypes were disrupted. Here we show that both the alpha2A- and alpha2C-subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. Alpha2A-adrenergic receptors inhibit transmitter release at high stimulation frequencies, whereas the alpha2C-subtype modulates neurotransmission at lower levels of nerve activity. Both low- and high-frequency regulation seem to be physiologically important, as mice lacking both alpha2A- and alpha2C-receptor subtypes have elevated plasma noradrenaline concentrations and develop cardiac hypertrophy with decreased left ventricular contractility by four months of age.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Brimonidine Tartrate
  • Cerebral Cortex / metabolism
  • Crosses, Genetic
  • Gene Deletion
  • Heart Atria
  • Hemodynamics
  • Mice
  • Myocardium / metabolism
  • Neural Inhibition / physiology
  • Norepinephrine / blood
  • Norepinephrine / metabolism
  • Quinoxalines / pharmacology
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / physiology*
  • Sympathetic Nervous System / physiology*
  • Synaptic Transmission / physiology*


  • Adra2a protein, mouse
  • Adra2c protein, mouse
  • Adrenergic alpha-Agonists
  • Quinoxalines
  • Receptors, Adrenergic, alpha-2
  • Brimonidine Tartrate
  • Norepinephrine