Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Two functionally distinct α2-adrenergic receptors regulate sympathetic neurotransmission

Nature volume 402, pages 181–184 (1999)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inhibition of noradrenaline release in atria by α2-receptor stimulation.
Figure 2: Autoinhibition of noradrenergic neurotransmission in isolated atria is mediated by α2A- and α2C-receptors.
Figure 3: Elevated plasma noradrenaline levels and cardiac phenotype of mice lacking α2-adrenergic-receptor subtypes.

Similar content being viewed by others

References

  1. Taylor,A. A. Autonomic control of cardiovascular function: clinical evaluation in health and disease. J. Clin. Pharmacol. 34, 363–374 (1994).

    Article  CAS  Google Scholar 

  2. Miller,R. J. Presynaptic recetors. Annu. Rev. Pharmacol. Toxicol. 38, 201–227 (1998).

    Article  CAS  Google Scholar 

  3. Langer,S. Z. 25 years since the discovery of presynaptic recetors: present knowledge and future perspectives. Trends Pharmacol. Sci. 18, 95–99 (1997).

    Article  CAS  Google Scholar 

  4. Starke,K., Göthert,M. & Kilbinger,H. Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol. Rev. 69, 864–989 (1989).

    Article  CAS  Google Scholar 

  5. Stjärne,L. Basic mechanisms and local modulation of nerve impulse-induced secretion of neurotransmitters from individual sympathetic nerve varicosities. Rev. Physiol. Biochem. Pharmacol. 112, 4–137 (1989).

    Google Scholar 

  6. Bylund,D. B. et al. International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol. Rev. 46, 121–136 (1994).

    CAS  PubMed  Google Scholar 

  7. Link,R. E. et al. Targeted inactivation of the gene encoding the mouse α2C-adrenoceptor homolog. Molec. Pharmacol. 48, 48–55 (1995).

    CAS  Google Scholar 

  8. Link,R. E. et al. Cardiovascular regulation in mice lacking α2-adrenergic receptor subtypes b and c. Science 273, 803–805 (1996).

    Article  ADS  CAS  Google Scholar 

  9. MacMillan,L. B., Hein,L., Smith,M. S., Piascik,M. T. & Limbird,L. E. Central hypotensive effects of the α2A-adrenergic receptor subtype. Science 273, 801–803 (1996).

    Article  ADS  CAS  Google Scholar 

  10. Sallinen,J. et al. Genetic alteration of α2C-adrenoceptor expression in mice: influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective α2-adrenoceptor agonist. Molec. Pharmacol. 51, 36–46 (1997).

    Article  CAS  Google Scholar 

  11. Sallinen,J., Haapalinna,A., Vitamaa,T., Kobilka,B. K. & Scheinin,M. Adrenergic α2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice. J. Neurosci. 18, 3035–3042 (1998).

    Article  CAS  Google Scholar 

  12. Altman,J. D. et al. Abnormal regulation of the sympathetic nervous system in α2A-adrenergic receptor knockout mice. Molec. Pharmacol. 56, 154–161 (1999).

    Article  CAS  Google Scholar 

  13. Singer,E. A. Transmitter release from brain slices elicited by single pulses: a powerful method to study presynaptic mechanisms. Trends Pharmacol. Sci. 9, 274–276 (1988).

    Article  CAS  Google Scholar 

  14. Wahl,C. A., Trendelenburg,A. U. & Starke,K. Presynaptic α2-autoreceptors in mouse heart atria: evidence for the α2D subtype. Naunyn-Schmiedeberg's Arch. Pharmacol. 354, 253–261 (1996).

    Article  CAS  Google Scholar 

  15. Trendelenburg,A. U., Limberger,N. & Starke,K. Presynaptic α2-autoreceptors in brain cortex: α2D in the rat and α2A in the rabbit. Naunyn-Schmiedeberg's Arch. Pharmacol. 348, 35–45 (1993).

    Article  CAS  Google Scholar 

  16. Trendelenburg,A. U. et al. A re-investigation of questionable subclassifications of presynaptic α2-autoreceptors: rat vena cava, rat atria, human kidney and guinea-pig urethra. Naunyn-Schmiedeberg's Arch. Pharmacol. 356, 721–737 (1997).

    Article  CAS  Google Scholar 

  17. Molderings,G. J. & Göthert,M. Subtype determination of presynaptic α2-autoreceptors in the rabbit pulmonary artery and human saphenous vein. Naunyn-Schmiedeberg's Arch. Pharmacol. 352, 483–490 (1995).

    Article  CAS  Google Scholar 

  18. Smith,K., Gavin,K. & Docherty,J. R. Investigation of the subtype of α2-adrenoceptor mediating prejunctional inhibition of cardioacceleration in the pithed rat heart. Br. J. Pharmacol. 115, 316–320 (1995).

    Article  CAS  Google Scholar 

  19. Link,R. E., Daunt,D., Barsh,G., Chruscinski,A. & Kobilka,B. Cloning of two mouse genes encoding α2-adrenergic receptor subtypes and identification of a single amino acid in the mouse α2-C10 homolog responsible for an interspecies variation in antagonist binding. Molec. Pharmacol. 42, 16–27 (1992).

    CAS  Google Scholar 

  20. McLachlan,E. M., Davies,P. J., Habler,H. J. & Jamieson,J. On-going and reflex synaptic events in rat superior cervical ganglion cells. J. Physiol (Lond.) 501, 165–181 (1997).

    Article  CAS  Google Scholar 

  21. Lakhlani,P. P. et al. Substitution of a mutant α2A-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc. Natl Acad. Sci. USA 94, 9950–9955 (1997).

    Article  ADS  CAS  Google Scholar 

  22. Packer,M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J. Am. Coll. Cardiol. 20, 248–254 (1992).

    Article  CAS  Google Scholar 

  23. Cohn,J. N. et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med. 311, 819–823 (1984).

    Article  CAS  Google Scholar 

  24. Lechat,P. et al. Clinical effects of β-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 98, 1184–1191 (1998).

    Article  CAS  Google Scholar 

  25. Hein,L., Barsh,G. S., Pratt,R. E., Dzau,V. J. & Kobilka,B. K. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature 377, 744–747 (1995).

    Article  ADS  CAS  Google Scholar 

  26. Limberger,N., Trendelenburg,A. A. & Starke,K. Subclassification of presynaptic α2-adrenoceptors: α2D-autoreceptors in mouse brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 352, 43–48 (1995).

    CAS  Google Scholar 

  27. Taube,H. D., Starke,K. & Borowski,E. Presynaptic receptor systems on the noradrenergic neurones of rat brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 299, 123–141 (1977).

    Article  CAS  Google Scholar 

  28. Graefe,K. H. et al. 1,1′-Diisopropyl-2,4′-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines. Naunyn-Schmiedeberg's Arch. Pharmacol. 356, 115–125 (1997).

    Article  CAS  Google Scholar 

  29. Engelhardt,S., Hein,L., Wiesmann,F. & Lohse,M. J. progressive hypertrophy and heart failure in β1-adrenergic receptor transgenic mice. Proc. Natl Acad. Sci. USA 96, 7059–7064 (1999).

    Article  ADS  CAS  Google Scholar 

  30. Hein,L. et al. Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc. Natl Acad. Sci. USA 94, 6391–6396 (1997).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft SFB355 (to L.H.) and the Howard Hughes Medical Institute (to B.K.). We thank K. Starke, A. U. Trendelenburg, M. J. Lohse and M. M. Bücheler) for consultation and assistance with transmitter release experiments; S. Engelhardt for assistance with the pathological analysis; R. Link for help with construction of the α2A-targeting vector; A. Chruscinski for help in characterizing the α2AC-KO mice; and K. H. Graefe and R. Wölfel for HPLC analysis of plasma noradrenaline levels.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Würzburg, Würzburg D, 97078, Germany

    Lutz Hein

  2. Howard Hughes Medical Institute and the Departments of Medicine and Molecular and Cellular Physiology, Stanford University, Stanford, 94305, California, USA

    John D. Altman & Brian K. Kobilka

Authors
  1. Lutz Hein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John D. Altman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian K. Kobilka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian K. Kobilka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hein, L., Altman, J. & Kobilka, B. Two functionally distinct α2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402, 181–184 (1999). https://doi.org/10.1038/46040

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/46040

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing