Abstract
IN sympathetic neurons, catecholamines interact with prejunctional α-adrenergic receptors to reduce delivery of transmitter to postjunctional target organs1-4. This autoinhibitory feedback is a general phenomenon seen in diverse neurons containing a variety of transmitters2-4. The underlying mechanisms of α-adrenergic inhibition are not clear, although decreases in cyclic AMP and cAMP-mediated phosphorylation have been implicated1-4 (compare ref. 5). We have studied depolarization-induced catecholamine release and calcium-channel currents in frog sympathetic neurons. Here we show that α-adrenergic inhibition of transmitter release can be explained by inhibition of Ca2+-channel currents and not by modulation of intracellular proteins. Noradrenaline strongly reduces the activity of N-type Ca2+ channels, the dominant calcium entry pathway triggering sympathetic transmitter release6, whereas L-type Ca2+ channels are not significantly inhibited. The down-modulation of N-type channels involves changes in rapid gating kinetics but not in unitary flux. This is the first detailed description of inhibition of a high-voltage activated neuronal Ca2+ channel at the single-channel level. The coupling between α-adrenergic receptors and N-type channels involves a G protein, but not a readily diffusible cytoplasmic messenger or protein kinase C, and may be well suited for rapid and spatially localized feedback-control of transmitter release.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Langer, S. Z. Pharmac. Rev. 32, 337–362 (1981).
Starke, K. Rev. Physiol. Biochem. Pharmac. 107, 73–146 (1987).
Mulder, A. H., Frankhuyzen, A. L., Stoof, J. C., Werner, J. & Schoffelmeer, A. N. M. in Catecholamines: Neuropharmacology and Central Nervous System—Theoretical Aspects, 47–58 (Liss, New York, 1984).
Illes, P. Neuroscience 17, 909–928 (1986).
Johnston, H., Majewski, H. & Musgrave, I. F. Br. J. Pharmac. 91, 773–781 (1987).
Hirning, L. D. et al., Science 239, 57–61 (1988).
Suetake, K., Kojima, H., Inanaga, K. & Koketsu, K. Brain Res. 205, 436–440 (1981).
Canfield, D. R. & Dunkap, K. Br. J. Pharmac. 82, 557–563 (1984).
Docherty, R. J. & McFadzean, I. Eur. J. Neurosci. (in the press).
Llinas, R., McGuinness, T. L., Leonard, C. S., Sugimori, M. & Greengard, P. Proc. natn. Acad. Sci. U.S.A. 72, 187–190 (1985).
Hidaka, H., Inagai, M., Kawamoto, S. & Sasaki, Y. Biochemistry 23, 5036–5041 (1984).
DeLangen, C. D. J. & Mulder, A. H. Brain Res. 185, 399–408 (1980).
McAfee, D. A., Henon, B. K., Horn, J. P. & Yarowsky, P. Fedn. Proc. 40, 2246–2249 (1981).
Galvan, M. & Adams, P. R. Brain Res. 244, 135–144 (1982).
Marchetti, C., Carbone, E. & Lux, H. D. Pflugers Arch. ges. Physiol. 406, 104–111 (1986).
Holz, G. G., Rane, S. G. & Dunlap, K. Nature 319, 670–672 (1986).
Forscher, P., Oxford, G. S. & Schultz, D. J. Physiol., Lond. 379, 131–144 (1986).
Dunlap, K. & Fischbach, G. D. J. Physiol., Lond. 317, 519–535 (1981).
Bean, B. P. Nature, 340, 153–156 (1989).
Scott, R. H. & Dolphin, A. C. Nature 330, 760–762 (1987).
Hescheler, J., Rosenthal, W., Trautwein, W. & Schultz, G. Nature 325, 445–447 (1987).
Wanke, E. et al. Proc. natn. Acad. Sci. U.S.A. 84, 4313–4317 (1987).
Fox, A. P., Nowycky, M. C. & Tsien, R. W. J. Physiol., Lond. 394, 173–200 (1987).
Tsien, R. W., Lipscombe, D., Madison, D. V., Bley, K. R. & Fox, A. P. Trends Neurosci. 11, 431–438 (1988).
Plummer, M. R., Logothetic, D. E. & Hess, P. Neuron 2, 1453–1463 (1989).
Bean, B. P. A. Rev. Physiol. 51, 367–384 (1989).
Kongsamut, S., Lipscombe, D. & Tsien, R. W. Ann. N.Y. Acad. Sci. 560, 312–333 (1989).
Anderson, C. S. & Dunlap, K. Soc. Neurosci. Abstr. 14, 644 (1988).
Lipscombe, D., Bley, K. R. & Tsien, R. W. Soc. Neurosci. Abstr. 14, 153 (1988).
Perney, T. M., Hirning, L. D., Leeman, S. E. & Miller, R. J. Proc. natn. Acad. Sci. U.S.A. 83, 6656–6659 (1986).
Lindgren, C. A., Moore, J. W. & Sostman, A. H. J. gen. Physiol. (Abstr). 92, 5 (1988).
Rane, S. G., Holz, G. G. & Dunlap, K. Pflugers Arch. ges Physiol. 409, 361–366 (1987).
Rane, S. G. & Dunlap, K. Proc. natn. Acad. Sci. U.S.A. 83, 184–188 (1986).
Williams, J. T., Henderson, G. & North, R. A. Neuroscience 14, 95–101 (1985).
Dunlap, K. Pflügers Arch. ges. Physiol. 403, 170–174 (1985).
Azuma, T., Binia, A. & Visscher, M. B. Am. J. Physiol. 209, 1287–1294 (1965).
Lipscombe, D. & Tsien, R. W. J. Physiol. 390, 84P.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lipscombe, D., Kongsamut, S. & Tsien, R. α-Adrenergic inhibition of sympathetic neurotransmitter release mediated by modulation of N-type calcium-channel gating. Nature 340, 639–642 (1989). https://doi.org/10.1038/340639a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/340639a0
This article is cited by
-
Complex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorder
Scientific Reports (2022)
-
A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity
Scientific Reports (2016)
-
Scanning mutagenesis of the I-II loop of the Cav2.2 calcium channel identifies residues Arginine 376 and Valine 416 as molecular determinants of voltage dependent G protein inhibition
Molecular Brain (2010)
-
Down-Modulation of Ca2+ Channels by Endogenously Released ATP and Opioids: from the Isolated Chromaffin Cell to the Slice of Adrenal Medullae
Cellular and Molecular Neurobiology (2010)
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.