Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission.
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.
Hein
L
L
Department of Pharmacology and Toxicology, University of Würzburg, Germany.
Altman
J D
JD
Kobilka
B K
BK
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D002540:Cerebral Cortex / Q000378:metabolism; D003433:Crosses, Genetic; D017353:Gene Deletion; D006325:Heart Atria; D006439:Hemodynamics; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
C547769:Adra2a protein, mouse; C547775:Adra2c protein, mouse; D000316:Adrenergic alpha-Agonists; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate; D009638:Norepinephrine