Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Nov;116(6):2757–2763. doi: 10.1111/j.1476-5381.1995.tb17238.x

Protein kinase C involvement in maintenance and modulation of noradrenaline release in the mouse brain cortex.

G E Schroeder 1, P Kotsonis 1, I F Musgrave 1, H Majewski 1
PMCID: PMC1909115  PMID: 8591001

Abstract

1. The role of protein kinase C in the modulation of noradrenaline release was investigated in mouse cortical slices which were pre-incubated with [3H]-noradrenaline. The aim was to investigate the hypothesis that protein kinase C is activated during high levels of transmitter release to maintain transmitter output. 2. The protein kinase C activators, phorbol myristate acetate (0.01-0.3 microM) and to a greater extent 4 beta-phorbol 12,13-dibutyrate (0.01-0.3 microM) significantly enhanced stimulation-induced noradrenaline release whereas 4 alpha-phorbol 12,13-dibutyrate (0.1 microM) which does not activate protein kinase C was without effect. The effect of the protein kinase C activator, phorbol myristate acetate, on noradrenaline release was attenuated by the protein kinase C inhibitor, polymyxin B (21 microM) which by itself inhibited stimulation-induced noradrenaline release. 3. Protein kinase C was down-regulated by 10 h exposure of the cortical slices to 4 beta-phorbol 12,13-dibutyrate (1 microM). In this case the facilitatory effect of 4 beta-phorbol 12,13-dibutyrate (0.1 microM) on noradrenaline release was abolished as was the inhibitory effect produced by polymyxin B. This indicates that polymyxin B was acting selectively at protein kinase C. 4. The inhibitory effect of polymyxin B on noradrenaline release, when expressed as a percentage of the appropriate frequency control, was constant at 1, 5 and 10 Hz. Furthermore, the ratio of release at 5 Hz to that at 10 Hz was not altered by protein kinase C down-regulation, indicating that there is no additional effect of protein kinase C at higher stimulation frequencies. 5. When transmitter release was elevated by blocking alpha 2-adrenoceptor auto-inhibition with idazoxan (0.1 microM) or K+ channels with tetraethylammonium (300 microM), the elevation in transmitter release was significantly attenuated by protein kinase C down-regulation, suggesting an involvement of protein kinase C. 6. We conclude that protein kinase C is involved in the modulation of noradrenaline release over a wide range of stimulation frequencies, in addition to a role when noradrenaline release is elevated by presynaptic mechanisms.

Full text

PDF
2757

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARMSTRONG C. M., BINSTOCK L. ANOMALOUS RECTIFICATION IN THE SQUID GIANT AXON INJECTED WITH TETRAETHYLAMMONIUM CHLORIDE. J Gen Physiol. 1965 May;48:859–872. doi: 10.1085/jgp.48.5.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adams J. C., Gullick W. J. Differences in phorbol-ester-induced down-regulation of protein kinase C between cell lines. Biochem J. 1989 Feb 1;257(3):905–911. doi: 10.1042/bj2570905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allgaier C., Hertting G., Huang H. Y., Jackisch R. Protein kinase C activation and alpha 2-autoreceptor-modulated release of noradrenaline. Br J Pharmacol. 1987 Sep;92(1):161–172. doi: 10.1111/j.1476-5381.1987.tb11308.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Allgaier C., Hertting G. Polymyxin B, a selective inhibitor of protein kinase C, diminishes the release of noradrenaline and the enhancement of release caused by phorbol 12,13-butyrate. Naunyn Schmiedebergs Arch Pharmacol. 1986 Oct;334(2):218–221. doi: 10.1007/BF00505825. [DOI] [PubMed] [Google Scholar]
  5. Allgaier C., Hertting G., Singer E. A. A detailed study on the effects of protein kinase C activation on alpha-2 adrenoceptor-coupled modulation of norepinephrine release in hippocampus. J Pharmacol Exp Ther. 1991 Jul 1;258(1):143–148. [PubMed] [Google Scholar]
  6. Allgaier C., Von Kügelgen O., Hertting G. Enhancement of noradrenaline release by 12-O-tetradecanoyl phorbol-13-acetate, an activator of protein kinase C. Eur J Pharmacol. 1986 Oct 7;129(3):389–392. doi: 10.1016/0014-2999(86)90454-1. [DOI] [PubMed] [Google Scholar]
  7. Bader M. F., Sontag J. M., Thiersé D., Aunis D. A reassessment of guanine nucleotide effects on catecholamine secretion from permeabilized adrenal chromaffin cells. J Biol Chem. 1989 Oct 5;264(28):16426–16434. [PubMed] [Google Scholar]
  8. Brasch H. Influence of phorbol esters on stimulation-induced noradrenaline release and contractile force of isolated guinea-pig atria. Basic Res Cardiol. 1991 May-Jun;86(3):283–290. doi: 10.1007/BF02190608. [DOI] [PubMed] [Google Scholar]
  9. Bucher B., Neuburger J., Illes P. Protein kinase C and alpha 2-adrenoceptor-mediated inhibition of noradrenaline release from the rat tail artery. J Cardiovasc Pharmacol. 1991 Jun;17(6):913–915. doi: 10.1097/00005344-199106000-00008. [DOI] [PubMed] [Google Scholar]
  10. Burgess G. M., Mullaney I., McNeill M., Dunn P. M., Rang H. P. Second messengers involved in the mechanism of action of bradykinin in sensory neurons in culture. J Neurosci. 1989 Sep;9(9):3314–3325. doi: 10.1523/JNEUROSCI.09-09-03314.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Daschmann B., Allgaier C., Nakov R., Hertting G. Staurosporine counteracts the phorbol ester-induced enhancement of neurotransmitter release in hippocampus. Arch Int Pharmacodyn Ther. 1988 Nov-Dec;296:232–245. [PubMed] [Google Scholar]
  12. Dekker L. V., De Graan P. N., Versteeg D. H., Oestreicher A. B., Gispen W. H. Phosphorylation of B-50 (GAP43) is correlated with neurotransmitter release in rat hippocampal slices. J Neurochem. 1989 Jan;52(1):24–30. doi: 10.1111/j.1471-4159.1989.tb10893.x. [DOI] [PubMed] [Google Scholar]
  13. Haass M., Förster C., Richardt G., Kranzhöfer R., Schömig A. Role of calcium channels and protein kinase C for release of norepinephrine and neuropeptide Y. Am J Physiol. 1990 Nov;259(5 Pt 2):R925–R930. doi: 10.1152/ajpregu.1990.259.5.R925. [DOI] [PubMed] [Google Scholar]
  14. Huang H. Y., Allgaier C., Hertting G., Jackisch R. Phorbol ester-mediated enhancement of hippocampal noradrenaline release: which ion channels are involved? Eur J Pharmacol. 1988 Aug 24;153(2-3):175–184. doi: 10.1016/0014-2999(88)90604-8. [DOI] [PubMed] [Google Scholar]
  15. Ishac E. J., De Luca A. The influence of activation or inhibition of protein kinase C on the release of radioactivity from rat isolated atria labelled with [3H]-noradrenaline. Br J Pharmacol. 1988 Jul;94(3):713–720. doi: 10.1111/j.1476-5381.1988.tb11580.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Johnstone S. A., Hubaishy I., Waisman D. M. Phosphorylation of annexin II tetramer by protein kinase C inhibits aggregation of lipid vesicles by the protein. J Biol Chem. 1992 Dec 25;267(36):25976–25981. [PubMed] [Google Scholar]
  17. Kuo J. F., Raynor R. L., Mazzei G. J., Schatzman R. C., Turner R. S., Kem W. R. Cobra polypeptide cytotoxin I and marine worm polypeptide cytotoxin A-IV are potent and selective inhibitors of phospholipid-sensitive Ca2+-dependent protein kinase. FEBS Lett. 1983 Mar 7;153(1):183–186. doi: 10.1016/0014-5793(83)80144-6. [DOI] [PubMed] [Google Scholar]
  18. Matthies H. J., Palfrey H. C., Hirning L. D., Miller R. J. Down regulation of protein kinase C in neuronal cells: effects on neurotransmitter release. J Neurosci. 1987 Apr;7(4):1198–1206. doi: 10.1523/JNEUROSCI.07-04-01198.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mazzei G. J., Katoh N., Kuo J. F. Polymyxin B is a more selective inhibitor for phospholipid-sensitive Ca2+-dependent protein kinase than for calmodulin-sensitive Ca2+-dependent protein kinase. Biochem Biophys Res Commun. 1982 Dec 31;109(4):1129–1133. doi: 10.1016/0006-291x(82)91894-0. [DOI] [PubMed] [Google Scholar]
  20. Musgrave I. F., Majewski H. Effect of phorbol esters and polymyxin B on modulation of noradrenaline release in mouse atria. Naunyn Schmiedebergs Arch Pharmacol. 1989 Jan-Feb;339(1-2):48–53. doi: 10.1007/BF00165125. [DOI] [PubMed] [Google Scholar]
  21. Nichols R. A., Haycock J. W., Wang J. K., Greengard P. Phorbol ester enhancement of neurotransmitter release from rat brain synaptosomes. J Neurochem. 1987 Feb;48(2):615–621. doi: 10.1111/j.1471-4159.1987.tb04137.x. [DOI] [PubMed] [Google Scholar]
  22. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. doi: 10.1126/science.1411571. [DOI] [PubMed] [Google Scholar]
  23. Oda T., Shearman M. S., Nishizuka Y. Synaptosomal protein kinase C subspecies: B. Down-regulation promoted by phorbol ester and its effect on evoked norepinephrine release. J Neurochem. 1991 Apr;56(4):1263–1269. doi: 10.1111/j.1471-4159.1991.tb11420.x. [DOI] [PubMed] [Google Scholar]
  24. Rüegg U. T., Burgess G. M. Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends Pharmacol Sci. 1989 Jun;10(6):218–220. doi: 10.1016/0165-6147(89)90263-0. [DOI] [PubMed] [Google Scholar]
  25. Shearman M. S., Sekiguchi K., Nishizuka Y. Modulation of ion channel activity: a key function of the protein kinase C enzyme family. Pharmacol Rev. 1989 Jun;41(2):211–237. [PubMed] [Google Scholar]
  26. Shuntoh H., Tanaka C. Activation of protein kinase C potentiates norepinephrine release from sinus node. Am J Physiol. 1986 Dec;251(6 Pt 1):C833–C840. doi: 10.1152/ajpcell.1986.251.6.C833. [DOI] [PubMed] [Google Scholar]
  27. Shuntoh H., Taniyama K., Fukuzaki H., Tanaka C. Inhibition by cyclic AMP of phorbol ester-potentiated norepinephrine release from guinea pig brain cortical synaptosomes. J Neurochem. 1988 Nov;51(5):1565–1572. doi: 10.1111/j.1471-4159.1988.tb01126.x. [DOI] [PubMed] [Google Scholar]
  28. Stabel S., Parker P. J. Protein kinase C. Pharmacol Ther. 1991;51(1):71–95. doi: 10.1016/0163-7258(91)90042-k. [DOI] [PubMed] [Google Scholar]
  29. Starke K., Göthert M., Kilbinger H. Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev. 1989 Jul;69(3):864–989. doi: 10.1152/physrev.1989.69.3.864. [DOI] [PubMed] [Google Scholar]
  30. Takata Y., Ozawa J., Kato H. Presynaptic sites of isolated canine saphenous veins are more sensitive to protein kinase C than postsynaptic ones. Jpn J Pharmacol. 1991 Jul;56(3):337–348. doi: 10.1254/jjp.56.337. [DOI] [PubMed] [Google Scholar]
  31. Versteeg D. H., Florijn W. J. Phorbol 12,13-dibutyrate enhances electrically stimulated neuromessenger release from rat dorsal hippocampal slices in vitro. Life Sci. 1987 Mar 30;40(13):1237–1243. doi: 10.1016/0024-3205(87)90579-0. [DOI] [PubMed] [Google Scholar]
  32. Versteeg D. H., Ulenkate H. J. Basal and electrically stimulated release of [3H]noradrenaline and [3H]dopamine from rat amygdala slices in vitro: effects of 4 beta-phorbol 12,13-dibutyrate, 4 alpha-phorbol 12,13-didecanoate and polymyxin B. Brain Res. 1987 Jul 28;416(2):343–348. doi: 10.1016/0006-8993(87)90916-4. [DOI] [PubMed] [Google Scholar]
  33. Wakade A. R., Malhotra R. K., Wakade T. D. Phorbol ester, an activator of protein kinase C, enhances calcium-dependent release of sympathetic neurotransmitter. Naunyn Schmiedebergs Arch Pharmacol. 1985 Oct;331(1):122–124. doi: 10.1007/BF00498863. [DOI] [PubMed] [Google Scholar]
  34. Wakade T. D., Bhave S. V., Bhave A. S., Malhotra R. K., Wakade A. R. Depolarizing stimuli and neurotransmitters utilize separate pathways to activate protein kinase C in sympathetic neurons. J Biol Chem. 1991 Apr 5;266(10):6424–6428. [PubMed] [Google Scholar]
  35. Wang W., Creutz C. E. Regulation of the chromaffin granule aggregating activity of annexin I by phosphorylation. Biochemistry. 1992 Oct 20;31(41):9934–9939. doi: 10.1021/bi00156a011. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES