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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 Nov;86(21):8550–8554. doi: 10.1073/pnas.86.21.8550

Inhibition of Ca2+/calmodulin-dependent protein kinase II by arachidonic acid and its metabolites.

D Piomelli 1, J K Wang 1, T S Sihra 1, A C Nairn 1, A J Czernik 1, P Greengard 1
PMCID: PMC298320  PMID: 2554319

Abstract

A variety of evidence indicates that activation of Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) in nerve terminals leads to enhanced neurotransmitter release. Arachidonic acid and its 12-lipoxygenase metabolite, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), have been suggested to act as second messengers mediating presynaptic inhibition of neurotransmitter release. In the present study it was found that CaM-kinase II, purified from rat brain cortex, was inhibited both by arachidonic acid (IC50 = 24 microM) and by 12-HPETE (IC50 = 0.7 microM). Neither substance inhibited CaM-kinase I or III, protein kinase C, or the catalytic subunit of cAMP-dependent protein kinase. Specific inhibition of Ca2+/calmodulin-dependent protein phosphorylation by arachidonic acid was also demonstrated in intact synaptic terminals (synaptosomes) isolated from rat forebrain. These results suggest that arachidonate and its metabolites may modulate synaptic function through the inhibition of CaM-kinase II-dependent protein phosphorylation.

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Selected References

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  1. Augustine G. J., Charlton M. P., Smith S. J. Calcium action in synaptic transmitter release. Annu Rev Neurosci. 1987;10:633–693. doi: 10.1146/annurev.ne.10.030187.003221. [DOI] [PubMed] [Google Scholar]
  2. Bähler M., Greengard P. Synapsin I bundles F-actin in a phosphorylation-dependent manner. Nature. 1987 Apr 16;326(6114):704–707. doi: 10.1038/326704a0. [DOI] [PubMed] [Google Scholar]
  3. Colbran R. J., Fong Y. L., Schworer C. M., Soderling T. R. Regulatory interactions of the calmodulin-binding, inhibitory, and autophosphorylation domains of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1988 Dec 5;263(34):18145–18151. [PubMed] [Google Scholar]
  4. Czernik A. J., Pang D. T., Greengard P. Amino acid sequences surrounding the cAMP-dependent and calcium/calmodulin-dependent phosphorylation sites in rat and bovine synapsin I. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7518–7522. doi: 10.1073/pnas.84.21.7518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. De Camilli P., Greengard P. Synapsin I: a synaptic vesicle-associated neuronal phosphoprotein. Biochem Pharmacol. 1986 Dec 15;35(24):4349–4357. doi: 10.1016/0006-2952(86)90747-1. [DOI] [PubMed] [Google Scholar]
  6. Dumuis A., Sebben M., Haynes L., Pin J. P., Bockaert J. NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature. 1988 Nov 3;336(6194):68–70. doi: 10.1038/336068a0. [DOI] [PubMed] [Google Scholar]
  7. Gammon C. M., Allen A. C., Morell P. Bradykinin stimulates phosphoinositide hydrolysis and mobilization of arachidonic acid in dorsal root ganglion neurons. J Neurochem. 1989 Jul;53(1):95–101. doi: 10.1111/j.1471-4159.1989.tb07299.x. [DOI] [PubMed] [Google Scholar]
  8. Giaume C., Randriamampita C., Trautmann A. Arachidonic acid closes gap junction channels in rat lacrimal glands. Pflugers Arch. 1989 Jan;413(3):273–279. doi: 10.1007/BF00583541. [DOI] [PubMed] [Google Scholar]
  9. Gorelick F. S., Wang J. K., Lai Y., Nairn A. C., Greengard P. Autophosphorylation and activation of Ca2+/calmodulin-dependent protein kinase II in intact nerve terminals. J Biol Chem. 1988 Nov 25;263(33):17209–17212. [PubMed] [Google Scholar]
  10. Grand R. J., Perry S. V., Weeks R. A. Troponin C-like proteins (calmodulins) from mammalian smooth muscle and other tissues. Biochem J. 1979 Feb 1;177(2):521–529. doi: 10.1042/bj1770521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hemmings H. C., Jr, Greengard P., Tung H. Y., Cohen P. DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature. 1984 Aug 9;310(5977):503–505. doi: 10.1038/310503a0. [DOI] [PubMed] [Google Scholar]
  12. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  13. Kaczmarek L. K., Jennings K. R., Strumwasser F., Nairn A. C., Walter U., Wilson F. D., Greengard P. Microinjection of catalytic subunit of cyclic AMP-dependent protein kinase enhances calcium action potentials of bag cell neurons in cell culture. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7487–7491. doi: 10.1073/pnas.77.12.7487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kim D., Clapham D. E. Potassium channels in cardiac cells activated by arachidonic acid and phospholipids. Science. 1989 Jun 9;244(4909):1174–1176. doi: 10.1126/science.2727703. [DOI] [PubMed] [Google Scholar]
  15. Kim D., Lewis D. L., Graziadei L., Neer E. J., Bar-Sagi D., Clapham D. E. G-protein beta gamma-subunits activate the cardiac muscarinic K+-channel via phospholipase A2. Nature. 1989 Feb 9;337(6207):557–560. doi: 10.1038/337557a0. [DOI] [PubMed] [Google Scholar]
  16. Kurachi Y., Ito H., Sugimoto T., Shimizu T., Miki I., Ui M. Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel. Nature. 1989 Feb 9;337(6207):555–557. doi: 10.1038/337555a0. [DOI] [PubMed] [Google Scholar]
  17. Kwiatkowski A. P., King M. M. Autophosphorylation of the type II calmodulin-dependent protein kinase is essential for formation of a proteolytic fragment with catalytic activity. Implications for long-term synaptic potentiation. Biochemistry. 1989 Jun 27;28(13):5380–5385. doi: 10.1021/bi00439a010. [DOI] [PubMed] [Google Scholar]
  18. Lai Y., Nairn A. C., Greengard P. Autophosphorylation reversibly regulates the Ca2+/calmodulin-dependence of Ca2+/calmodulin-dependent protein kinase II. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4253–4257. doi: 10.1073/pnas.83.12.4253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Llinás R., McGuinness T. L., Leonard C. S., Sugimori M., Greengard P. Intraterminal injection of synapsin I or calcium/calmodulin-dependent protein kinase II alters neurotransmitter release at the squid giant synapse. Proc Natl Acad Sci U S A. 1985 May;82(9):3035–3039. doi: 10.1073/pnas.82.9.3035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. McGuinness T. L., Lai Y., Greengard P. Ca2+/calmodulin-dependent protein kinase II. Isozymic forms from rat forebrain and cerebellum. J Biol Chem. 1985 Feb 10;260(3):1696–1704. [PubMed] [Google Scholar]
  21. McPhail L. C., Clayton C. C., Snyderman R. A potential second messenger role for unsaturated fatty acids: activation of Ca2+-dependent protein kinase. Science. 1984 May 11;224(4649):622–625. doi: 10.1126/science.6231726. [DOI] [PubMed] [Google Scholar]
  22. Nairn A. C., Bhagat B., Palfrey H. C. Identification of calmodulin-dependent protein kinase III and its major Mr 100,000 substrate in mammalian tissues. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7939–7943. doi: 10.1073/pnas.82.23.7939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nairn A. C., Greengard P. Purification and characterization of Ca2+/calmodulin-dependent protein kinase I from bovine brain. J Biol Chem. 1987 May 25;262(15):7273–7281. [PubMed] [Google Scholar]
  24. Naor Z., Shearman M. S., Kishimoto A., Nishizuka Y. Calcium-independent activation of hypothalamic type I protein kinase C by unsaturated fatty acids. Mol Endocrinol. 1988 Nov;2(11):1043–1048. doi: 10.1210/mend-2-11-1043. [DOI] [PubMed] [Google Scholar]
  25. Norman J. A., Drummond A. H., Moser P. Inhibition of calcium-dependent regulator-stimulated phosphodiesterase activity by neuroleptic drugs is unrelated to their clinical efficacy. Mol Pharmacol. 1979 Nov;16(3):1089–1094. [PubMed] [Google Scholar]
  26. Ordway R. W., Walsh J. V., Jr, Singer J. J. Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells. Science. 1989 Jun 9;244(4909):1176–1179. doi: 10.1126/science.2471269. [DOI] [PubMed] [Google Scholar]
  27. Piomelli D., Shapiro E., Feinmark S. J., Schwartz J. H. Metabolites of arachidonic acid in the nervous system of Aplysia: possible mediators of synaptic modulation. J Neurosci. 1987 Nov;7(11):3675–3686. doi: 10.1523/JNEUROSCI.07-11-03675.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Piomelli D., Shapiro E., Zipkin R., Schwartz J. H., Feinmark S. J. Formation and action of 8-hydroxy-11,12-epoxy-5,9,14-icosatrienoic acid in Aplysia: a possible second messenger in neurons. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1721–1725. doi: 10.1073/pnas.86.5.1721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Piomelli D., Volterra A., Dale N., Siegelbaum S. A., Kandel E. R., Schwartz J. H., Belardetti F. Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells. Nature. 1987 Jul 2;328(6125):38–43. doi: 10.1038/328038a0. [DOI] [PubMed] [Google Scholar]
  30. Sautebin L., Spagnuolo C., Galli C., Galli G. A mass fragmentographic procedure for the simultaneous determination of HETE and PGF2alpha in the central nervous system. Prostaglandins. 1978 Dec;16(6):985–988. doi: 10.1016/0090-6980(78)90115-6. [DOI] [PubMed] [Google Scholar]
  31. Schulman H. The multifunctional Ca2+/calmodulin-dependent protein kinase. Adv Second Messenger Phosphoprotein Res. 1988;22:39–112. [PubMed] [Google Scholar]
  32. Stewart A. A., Cohen P. Protein phosphatase-2B from rabbit skeletal muscle: a Ca2+-dependent, calmodulin-stimulated enzyme. Methods Enzymol. 1988;159:409–416. doi: 10.1016/0076-6879(88)59040-7. [DOI] [PubMed] [Google Scholar]
  33. Wang J. K., Walaas S. I., Greengard P. Protein phosphorylation in nerve terminals: comparison of calcium/calmodulin-dependent and calcium/diacylglycerol-dependent systems. J Neurosci. 1988 Jan;8(1):281–288. doi: 10.1523/JNEUROSCI.08-01-00281.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wolfe L. S. Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of carbon-20 unsaturated fatty acids. J Neurochem. 1982 Jan;38(1):1–14. doi: 10.1111/j.1471-4159.1982.tb10847.x. [DOI] [PubMed] [Google Scholar]
  35. Wolfe L. S., Pellerin L. Arachidonic acid metabolites in the rat and human brain. New findings on the metabolism of prostaglandin D2 and lipoxygenase products. Ann N Y Acad Sci. 1989;559:74–83. doi: 10.1111/j.1749-6632.1989.tb22599.x. [DOI] [PubMed] [Google Scholar]
  36. Woodgett J. R., Hunter T. Isolation and characterization of two distinct forms of protein kinase C. J Biol Chem. 1987 Apr 5;262(10):4836–4843. [PubMed] [Google Scholar]

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