Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2000 Nov 1;351(Pt 3):709–716.

Negative regulation of cytosolic phospholipase A(2) by melatonin in the rat pineal gland.

B Li 1, H Zhang 1, M Akbar 1, H Y Kim 1
PMCID: PMC1221411  PMID: 11042126

Abstract

In this paper evidence that supports a new role for melatonin as a negative endogenous regulator of cytosolic phospholipase A(2) (cPLA(2)) is presented. When rat pineal glands were incubated in culture, time-dependent release of arachidonic acid (AA) was observed, which was significantly inhibited by a known 85-kDa cPLA(2) inhibitor, methyl arachidonyl fluorophosphonate. Co-incubation with melatonin inhibited the AA release in a concentration-dependent manner, and this decrease was accompanied by a reduction of cPLA(2) protein and mRNA expression. Melatonin-receptor agonists, 2-iodo-N-butanoyl-5-methoxytryptamine and 5-methoxycarbonylamino-N-acetyltryptamine, also decreased AA release and cPLA(2) protein and mRNA levels, while pre-incubation with the melatonin receptor antagonists luzindole and 2-phenylmelatonin abolished the melatonin effect. In vivo, as melatonin production reflected a typical diurnal variation, endogenous non-esterified AA and cPLA(2) mRNA levels in the rat pineal gland showed an off-phase diurnal pattern in relation to melatonin levels. Intravenous administration of isoproterenol, which has been shown to elevate melatonin production, also decreased the levels of non-esterified AA and cPLA(2) mRNA significantly. Direct administration of melatonin to rats by intravenous injection decreased the levels of non-esterified AA, cPLA(2) protein and mRNA in rat pineal glands. In conclusion, melatonin endogenously down-regulates cPLA(2) expression, presumably through melatonin-receptor-mediated processes.

Full Text

The Full Text of this article is available as a PDF (197.9 KB).

Selected References

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

  1. BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
  2. Balsinde J., Dennis E. A. Function and inhibition of intracellular calcium-independent phospholipase A2. J Biol Chem. 1997 Jun 27;272(26):16069–16072. doi: 10.1074/jbc.272.26.16069. [DOI] [PubMed] [Google Scholar]
  3. Bayon Y., Hernandez M., Alonso A., Nuñez L., Garcia-Sancho J., Leslie C., Sanchez Crespo M., Nieto M. L. Cytosolic phospholipase A2 is coupled to muscarinic receptors in the human astrocytoma cell line 1321N1: characterization of the transducing mechanism. Biochem J. 1997 Apr 1;323(Pt 1):281–287. doi: 10.1042/bj3230281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Becker-André M., Wiesenberg I., Schaeren-Wiemers N., André E., Missbach M., Saurat J. H., Carlberg C. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 1994 Nov 18;269(46):28531–28534. [PubMed] [Google Scholar]
  5. Börsch-Haubold A. G. Regulation of cytosolic phospholipase A2 by phosphorylation. Biochem Soc Trans. 1998 Aug;26(3):350–354. doi: 10.1042/bst0260350. [DOI] [PubMed] [Google Scholar]
  6. Cardinali D. P., Vacas M. I., Keller Sarmiento M. I., Etchegoyen G. S., Pereyra E. N., Chuluyan H. E. Neuroendocrine integrative mechanisms in mammalian pineal gland: effects of steroid and adenohypophysial hormones on melatonin synthesis in vitro. J Steroid Biochem. 1987;27(1-3):565–571. doi: 10.1016/0022-4731(87)90355-4. [DOI] [PubMed] [Google Scholar]
  7. Chaminade B., Le Balle F., Fourcade O., Nauze M., Delagebeaudeuf C., Gassama-Diagne A., Simon M. F., Fauvel J., Chap H. New developments in phospholipase A2. Lipids. 1999;34 (Suppl):S49–S55. doi: 10.1007/BF02562228. [DOI] [PubMed] [Google Scholar]
  8. Clark J. D., Schievella A. R., Nalefski E. A., Lin L. L. Cytosolic phospholipase A2. J Lipid Mediat Cell Signal. 1995 Oct;12(2-3):83–117. doi: 10.1016/0929-7855(95)00012-f. [DOI] [PubMed] [Google Scholar]
  9. Deguchi T. Role of the beta adrenergic receptor in the elevation of adenosine cyclic 3',5'-monophosphate and induction of serotonin N-acetyltransferase in rat pineal glands. Mol Pharmacol. 1973 Mar;9(2):184–190. [PubMed] [Google Scholar]
  10. Dekker L. V., Parker P. J. Regulated binding of the protein kinase C substrate GAP-43 to the V0/C2 region of protein kinase C-delta. J Biol Chem. 1997 May 9;272(19):12747–12753. doi: 10.1074/jbc.272.19.12747. [DOI] [PubMed] [Google Scholar]
  11. Dennis E. A. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem. 1994 May 6;269(18):13057–13060. [PubMed] [Google Scholar]
  12. Dubocovich M. L. Melatonin receptors: are there multiple subtypes? Trends Pharmacol Sci. 1995 Feb;16(2):50–56. doi: 10.1016/s0165-6147(00)88978-6. [DOI] [PubMed] [Google Scholar]
  13. Esposti D., Mariani M., Demartini G., Lucini V., Fraschini F., Mancia M. Modulation of melatonin secretion by acetyl-L-carnitine in adult and old rats. J Pineal Res. 1994 Oct;17(3):132–136. doi: 10.1111/j.1600-079x.1994.tb00124.x. [DOI] [PubMed] [Google Scholar]
  14. Exton J. H. Phosphatidylcholine breakdown and signal transduction. Biochim Biophys Acta. 1994 Apr 14;1212(1):26–42. doi: 10.1016/0005-2760(94)90186-4. [DOI] [PubMed] [Google Scholar]
  15. Gijón M. A., Leslie C. C. Regulation of arachidonic acid release and cytosolic phospholipase A2 activation. J Leukoc Biol. 1999 Mar;65(3):330–336. doi: 10.1002/jlb.65.3.330. [DOI] [PubMed] [Google Scholar]
  16. Hwang S. C., Jhon D. Y., Bae Y. S., Kim J. H., Rhee S. G. Activation of phospholipase C-gamma by the concerted action of tau proteins and arachidonic acid. J Biol Chem. 1996 Aug 2;271(31):18342–18349. doi: 10.1074/jbc.271.31.18342. [DOI] [PubMed] [Google Scholar]
  17. Iuvone P. M., Gan J. Melatonin receptor-mediated inhibition of cyclic AMP accumulation in chick retinal cell cultures. J Neurochem. 1994 Jul;63(1):118–124. doi: 10.1046/j.1471-4159.1994.63010118.x. [DOI] [PubMed] [Google Scholar]
  18. Kramer R. M., Sharp J. D. Structure, function and regulation of Ca2+-sensitive cytosolic phospholipase A2 (cPLA2). FEBS Lett. 1997 Jun 23;410(1):49–53. doi: 10.1016/s0014-5793(97)00322-0. [DOI] [PubMed] [Google Scholar]
  19. Laitinen J. T., Saavedra J. M. Characterization of melatonin receptors in the rat suprachiasmatic nuclei: modulation of affinity with cations and guanine nucleotides. Endocrinology. 1990 Apr;126(4):2110–2115. doi: 10.1210/endo-126-4-2110. [DOI] [PubMed] [Google Scholar]
  20. Leslie C. C. Properties and regulation of cytosolic phospholipase A2. J Biol Chem. 1997 Jul 4;272(27):16709–16712. doi: 10.1074/jbc.272.27.16709. [DOI] [PubMed] [Google Scholar]
  21. Lin L. L., Lin A. Y., Knopf J. L. Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6147–6151. doi: 10.1073/pnas.89.13.6147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lin L. L., Wartmann M., Lin A. Y., Knopf J. L., Seth A., Davis R. J. cPLA2 is phosphorylated and activated by MAP kinase. Cell. 1993 Jan 29;72(2):269–278. doi: 10.1016/0092-8674(93)90666-e. [DOI] [PubMed] [Google Scholar]
  23. Liscovitch M., Cantley L. C. Lipid second messengers. Cell. 1994 May 6;77(3):329–334. doi: 10.1016/0092-8674(94)90148-1. [DOI] [PubMed] [Google Scholar]
  24. Mennenga K., Ueck M., Reiter R. J. Immunohistological localization of melatonin in the pineal gland and retina of the rat. J Pineal Res. 1991 Apr;10(3):159–164. doi: 10.1111/j.1600-079x.1991.tb00834.x. [DOI] [PubMed] [Google Scholar]
  25. Murakami M., Kudo I., Inoue K. Secretory phospholipases A2. J Lipid Mediat Cell Signal. 1995 Oct;12(2-3):119–130. doi: 10.1016/0929-7855(95)00013-g. [DOI] [PubMed] [Google Scholar]
  26. Reiter R. J. Melatonin: the chemical expression of darkness. Mol Cell Endocrinol. 1991 Aug;79(1-3):C153–C158. doi: 10.1016/0303-7207(91)90087-9. [DOI] [PubMed] [Google Scholar]
  27. Reiter R. J. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev. 1991 May;12(2):151–180. doi: 10.1210/edrv-12-2-151. [DOI] [PubMed] [Google Scholar]
  28. Roshak A., Sathe G., Marshall L. A. Suppression of monocyte 85-kDa phospholipase A2 by antisense and effects on endotoxin-induced prostaglandin biosynthesis. J Biol Chem. 1994 Oct 21;269(42):25999–26005. [PubMed] [Google Scholar]
  29. Ross A. W., Barrett P., Mercer J. G., Morgan P. J. Melatonin suppresses the induction of AP-1 transcription factor components in the pars tuberalis of the pituitary. Mol Cell Endocrinol. 1996 Oct 14;123(1):71–80. doi: 10.1016/0303-7207(96)03897-x. [DOI] [PubMed] [Google Scholar]
  30. Shuttleworth T. J. Arachidonic acid activates the noncapacitative entry of Ca2+ during [Ca2+]i oscillations. J Biol Chem. 1996 Sep 6;271(36):21720–21725. doi: 10.1074/jbc.271.36.21720. [DOI] [PubMed] [Google Scholar]
  31. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  32. Steardo L., Monteleone P., d'Istria M., Serino I., Maj M., Cuomo V. (+)-N-allylnormetazocine enhances N-acetyltransferase activity and melatonin synthesis: preliminary evidence for a functional role of sigma receptors in the rat pineal gland. J Pharmacol Exp Ther. 1995 Nov;275(2):845–849. [PubMed] [Google Scholar]
  33. Steinhilber D., Brungs M., Werz O., Wiesenberg I., Danielsson C., Kahlen J. P., Nayeri S., Schräder M., Carlberg C. The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes. J Biol Chem. 1995 Mar 31;270(13):7037–7040. doi: 10.1074/jbc.270.13.7037. [DOI] [PubMed] [Google Scholar]
  34. Surette M. E., Dallaire N., Jean N., Picard S., Borgeat P. Mechanisms of the priming effect of lipopolysaccharides on the biosynthesis of leukotriene B4 in chemotactic peptide-stimulated human neutrophils. FASEB J. 1998 Nov;12(14):1521–1531. doi: 10.1096/fasebj.12.14.1521. [DOI] [PubMed] [Google Scholar]
  35. Uz T., Longone P., Manev H. Increased hippocampal 5-lipoxygenase mRNA content in melatonin-deficient, pinealectomized rats. J Neurochem. 1997 Nov;69(5):2220–2223. doi: 10.1046/j.1471-4159.1997.69052220.x. [DOI] [PubMed] [Google Scholar]
  36. Uz T., Manev H. Circadian expression of pineal 5-lipoxygenase mRNA. Neuroreport. 1998 Mar 30;9(5):783–786. doi: 10.1097/00001756-199803300-00003. [DOI] [PubMed] [Google Scholar]
  37. Vanecek J. Cellular mechanisms of melatonin action. Physiol Rev. 1998 Jul;78(3):687–721. doi: 10.1152/physrev.1998.78.3.687. [DOI] [PubMed] [Google Scholar]
  38. Vanecek J., Klein D. C. A subpopulation of neonatal gonadotropin-releasing hormone-sensitive pituitary cells is responsive to melatonin. Endocrinology. 1993 Jul;133(1):360–367. doi: 10.1210/endo.133.1.8319582. [DOI] [PubMed] [Google Scholar]
  39. Vanecek J., Vollrath L. Melatonin modulates diacylglycerol and arachidonic acid metabolism in the anterior pituitary of immature rats. Neurosci Lett. 1990 Mar 2;110(1-2):199–203. doi: 10.1016/0304-3940(90)90811-m. [DOI] [PubMed] [Google Scholar]
  40. Xing M., Insel P. A. Protein kinase C-dependent activation of cytosolic phospholipase A2 and mitogen-activated protein kinase by alpha 1-adrenergic receptors in Madin-Darby canine kidney cells. J Clin Invest. 1996 Mar 1;97(5):1302–1310. doi: 10.1172/JCI118546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zhang H., Akbar M., Kim H. Y. Melatonin: an endogenous negative modulator of 12-lipoxygenation in the rat pineal gland. Biochem J. 1999 Dec 1;344(Pt 2):487–493. [PMC free article] [PubMed] [Google Scholar]
  42. Zhang H., Hamilton J. H., Salem N., Jr, Kim H. Y. N-3 fatty acid deficiency in the rat pineal gland: effects on phospholipid molecular species composition and endogenous levels of melatonin and lipoxygenase products. J Lipid Res. 1998 Jul;39(7):1397–1403. [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES