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. 1996 Jun;118(4):1035–1043. doi: 10.1111/j.1476-5381.1996.tb15503.x

Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus.

D E Pellegrini-Giampietro 1, S A Torregrossa 1, F Moroni 1
PMCID: PMC1909512  PMID: 8799579

Abstract

1. Phospholipase D (PLD) is the key enzyme in a signal transduction pathway leading to the formation of the second messengers phosphatidic acid and diacylglycerol. In order to define the pharmacological profile of PLD-coupled metabotropic glutamate receptors (mGluRs), PLD activity was measured in slices of adult rat brain in the presence of mGluR agonists or antagonists. Activation of the phospholipase C (PLC) pathway by the same agents was also examined. 2. The mGluR-selective agonist (1S,3R)-l-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] induced a concentration-dependent (10-300 microM) activation of PLD in the hippocampus, neocortex, and striatum, but not in the cerebellum. The effect was particularly evident in hippocampal slices, which were thus used for all subsequent experiments. 3. The rank order of potencies for agonists stimulating the PLD response was: quisqualate > ibotenate > (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine > (1S,3R)-ACPD > L-cysteine sulphinic acid > L-aspartate > L-glutamate. L-(+)-2-Amino-4-phosphonobutyric acid and the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate failed to activate PLD. (RS)-3,5-dihydroxyphenylglycine (100300 microM), an agonist of mGluRs of the first group, stimulated PLC but inhibited the PLD response elicited by 100 microM (1S,3R)-ACPD. 4. (+)-alpha-Methyl-4-carboxyphenylglycine (0.1-1 mM), a competitive antagonist of mGluRs of the first and second group, elicited a significant PLD response. L-(+)-2-Amino-3-phosphonopropionic acid (1 mM), an antagonist of mGluRs of the first group, inhibited the 100 microM (1S,3R)-ACPD-induced PLC response but produced a robust stimulation of PLD. 5. 12-O-Tetradecanoylphorbol 13-acetic acid and phorbol 12,13-dibutyrate (PDBu), activators of protein kinase C, at 1 microM had a stimulatory effect on mGluRs linked to PLD but depressed (1S,3R)-ACPD-induced phosphoinositide hydrolysis. The protein kinase C inhibitor, staurosporine (1 and 10 microM) reduced PLD activation induced by 1 microM PDBu but not by 100 microM (1S,3R)-ACPD. 6. Our results suggest that PLD-linked mGluRs in rat hippocampus may be distinct from any known mGluR subtype coupled to PLC or adenylyl cyclase. Moreover, they indicate that independent mGluRs coupled to the PLC and PLD pathways exist and that mGluR agonists can stimulate PLD through a PKC-independent mechanism.

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Selected References

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

  1. Abe T., Sugihara H., Nawa H., Shigemoto R., Mizuno N., Nakanishi S. Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J Biol Chem. 1992 Jul 5;267(19):13361–13368. [PubMed] [Google Scholar]
  2. Alexander S. P., Curtis A. R., Hill S. J., Kendall D. A. Activation of a metabotropic excitatory amino acid receptor potentiates A2b adenosine receptor-stimulated cyclic AMP accumulation. Neurosci Lett. 1992 Nov 9;146(2):231–233. doi: 10.1016/0304-3940(92)90085-l. [DOI] [PubMed] [Google Scholar]
  3. Aramori I., Nakanishi S. Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron. 1992 Apr;8(4):757–765. doi: 10.1016/0896-6273(92)90096-v. [DOI] [PubMed] [Google Scholar]
  4. Billah M. M., Anthes J. C. The regulation and cellular functions of phosphatidylcholine hydrolysis. Biochem J. 1990 Jul 15;269(2):281–291. doi: 10.1042/bj2690281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Billah M. M., Pai J. K., Mullmann T. J., Egan R. W., Siegel M. I. Regulation of phospholipase D in HL-60 granulocytes. Activation by phorbol esters, diglyceride, and calcium ionophore via protein kinase- independent mechanisms. J Biol Chem. 1989 May 25;264(15):9069–9076. [PubMed] [Google Scholar]
  6. Boss V., Conn P. J. Metabotropic excitatory amino acid receptor activation stimulates phospholipase D in hippocampal slices. J Neurochem. 1992 Dec;59(6):2340–2343. doi: 10.1111/j.1471-4159.1992.tb10131.x. [DOI] [PubMed] [Google Scholar]
  7. Boss V., Nutt K. M., Conn P. J. L-cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity. Mol Pharmacol. 1994 Jun;45(6):1177–1182. [PubMed] [Google Scholar]
  8. Brabet I., Mary S., Bockaert J., Pin J. P. Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses. Neuropharmacology. 1995 Aug;34(8):895–903. doi: 10.1016/0028-3908(95)00079-l. [DOI] [PubMed] [Google Scholar]
  9. Canonico P. L., Favit A., Catania M. V., Nicoletti F. Phorbol esters attenuate glutamate-stimulated inositol phospholipid hydrolysis in neuronal cultures. J Neurochem. 1988 Oct;51(4):1049–1053. doi: 10.1111/j.1471-4159.1988.tb03067.x. [DOI] [PubMed] [Google Scholar]
  10. Catania M. V., Aronica E., Sortino M. A., Canonico P. L., Nicoletti F. Desensitization of metabotropic glutamate receptors in neuronal cultures. J Neurochem. 1991 Apr;56(4):1329–1335. doi: 10.1111/j.1471-4159.1991.tb11429.x. [DOI] [PubMed] [Google Scholar]
  11. Dumuis A., Pin J. P., Oomagari K., Sebben M., Bockaert J. Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature. 1990 Sep 13;347(6289):182–184. doi: 10.1038/347182a0. [DOI] [PubMed] [Google Scholar]
  12. Eaton S. A., Jane D. E., Jones P. L., Porter R. H., Pook P. C., Sunter D. C., Udvarhelyi P. M., Roberts P. J., Salt T. E., Watkins J. C. Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenylglycine and (RS)-alpha-methyl-4-carboxyphenylglycine. Eur J Pharmacol. 1993 Jan 15;244(2):195–197. doi: 10.1016/0922-4106(93)90028-8. [DOI] [PubMed] [Google Scholar]
  13. Hayashi Y., Sekiyama N., Nakanishi S., Jane D. E., Sunter D. C., Birse E. F., Udvarhelyi P. M., Watkins J. C. Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor subtypes. J Neurosci. 1994 May;14(5 Pt 2):3370–3377. doi: 10.1523/JNEUROSCI.14-05-03370.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holler T., Cappel E., Klein J., Löffelholz K. Glutamate activates phospholipase D in hippocampal slices of newborn and adult rats. J Neurochem. 1993 Oct;61(4):1569–1572. doi: 10.1111/j.1471-4159.1993.tb13659.x. [DOI] [PubMed] [Google Scholar]
  15. Holler T., Klein J., Löffelholz K. Phospholipase C and phospholipase D are independently activated in rat hippocampal slices. Biochem Pharmacol. 1994 Jan 20;47(2):411–414. doi: 10.1016/0006-2952(94)90033-7. [DOI] [PubMed] [Google Scholar]
  16. Ito I., Kohda A., Tanabe S., Hirose E., Hayashi M., Mitsunaga S., Sugiyama H. 3,5-Dihydroxyphenyl-glycine: a potent agonist of metabotropic glutamate receptors. Neuroreport. 1992 Nov;3(11):1013–1016. [PubMed] [Google Scholar]
  17. Kanaho Y., Kanoh H., Nozawa Y. Activation of phospholipase D in rabbit neutrophils by fMet-Leu-Phe is mediated by a pertussis toxin-sensitive GTP-binding protein that may be distinct from a phospholipase C-regulating protein. FEBS Lett. 1991 Feb 25;279(2):249–252. doi: 10.1016/0014-5793(91)80160-5. [DOI] [PubMed] [Google Scholar]
  18. Klein J., Chalifa V., Liscovitch M., Löffelholz K. Role of phospholipase D activation in nervous system physiology and pathophysiology. J Neurochem. 1995 Oct;65(4):1445–1455. doi: 10.1046/j.1471-4159.1995.65041445.x. [DOI] [PubMed] [Google Scholar]
  19. Llahi S., Fain J. N. Alpha 1-adrenergic receptor-mediated activation of phospholipase D in rat cerebral cortex. J Biol Chem. 1992 Feb 25;267(6):3679–3685. [PubMed] [Google Scholar]
  20. Löffelholz K. Receptor regulation of choline phospholipid hydrolysis. A novel source of diacylglycerol and phosphatidic acid. Biochem Pharmacol. 1989 May 15;38(10):1543–1549. doi: 10.1016/0006-2952(89)90299-2. [DOI] [PubMed] [Google Scholar]
  21. Nakanishi S. Molecular diversity of glutamate receptors and implications for brain function. Science. 1992 Oct 23;258(5082):597–603. doi: 10.1126/science.1329206. [DOI] [PubMed] [Google Scholar]
  22. Nicoletti F., Meek J. L., Iadarola M. J., Chuang D. M., Roth B. L., Costa E. Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus. J Neurochem. 1986 Jan;46(1):40–46. doi: 10.1111/j.1471-4159.1986.tb12922.x. [DOI] [PubMed] [Google Scholar]
  23. Pai J. K., Siegel M. I., Egan R. W., Billah M. M. Phospholipase D catalyzes phospholipid metabolism in chemotactic peptide-stimulated HL-60 granulocytes. J Biol Chem. 1988 Sep 5;263(25):12472–12477. [PubMed] [Google Scholar]
  24. Pellegrini-Giampietro D. E., Ruggiero M., Giannelli S., Chiarugi V. P., Moroni F. Morphine withdrawal in vitro: potentiation of agonist-dependent polyphosphoinositide breakdown. Eur J Pharmacol. 1988 May 10;149(3):297–306. doi: 10.1016/0014-2999(88)90660-7. [DOI] [PubMed] [Google Scholar]
  25. Pin J. P., Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995 Jan;34(1):1–26. doi: 10.1016/0028-3908(94)00129-g. [DOI] [PubMed] [Google Scholar]
  26. Prezeau L., Manzoni O., Homburger V., Sladeczek F., Curry K., Bockaert J. Characterization of a metabotropic glutamate receptor: direct negative coupling to adenylyl cyclase and involvement of a pertussis toxin-sensitive G protein. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8040–8044. doi: 10.1073/pnas.89.17.8040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Qian Z., Drewes L. R. Muscarinic acetylcholine receptor regulates phosphatidylcholine phospholipase D in canine brain. J Biol Chem. 1989 Dec 25;264(36):21720–21724. [PubMed] [Google Scholar]
  28. Roberts P. J. Pharmacological tools for the investigation of metabotropic glutamate receptors (mGluRs): phenylglycine derivatives and other selective antagonists--an update. Neuropharmacology. 1995 Aug;34(8):813–819. doi: 10.1016/0028-3908(95)00094-m. [DOI] [PubMed] [Google Scholar]
  29. Robinson M. B., Sinor J. D., Dowd L. A., Kerwin J. F., Jr Subtypes of sodium-dependent high-affinity L-[3H]glutamate transport activity: pharmacologic specificity and regulation by sodium and potassium. J Neurochem. 1993 Jan;60(1):167–179. doi: 10.1111/j.1471-4159.1993.tb05835.x. [DOI] [PubMed] [Google Scholar]
  30. Ryu S. H., Kim U. H., Wahl M. I., Brown A. B., Carpenter G., Huang K. P., Rhee S. G. Feedback regulation of phospholipase C-beta by protein kinase C. J Biol Chem. 1990 Oct 15;265(29):17941–17945. [PubMed] [Google Scholar]
  31. Schoepp D. D., Conn P. J. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci. 1993 Jan;14(1):13–20. doi: 10.1016/0165-6147(93)90107-u. [DOI] [PubMed] [Google Scholar]
  32. Schoepp D. D., Goldsworthy J., Johnson B. G., Salhoff C. R., Baker S. R. 3,5-dihydroxyphenylglycine is a highly selective agonist for phosphoinositide-linked metabotropic glutamate receptors in the rat hippocampus. J Neurochem. 1994 Aug;63(2):769–772. doi: 10.1046/j.1471-4159.1994.63020769.x. [DOI] [PubMed] [Google Scholar]
  33. Schoepp D. D., Johnson B. G., Monn J. A. Inhibition of cyclic AMP formation by a selective metabotropic glutamate receptor agonist. J Neurochem. 1992 Mar;58(3):1184–1186. doi: 10.1111/j.1471-4159.1992.tb09381.x. [DOI] [PubMed] [Google Scholar]
  34. Schoepp D. D., Johnson B. G. Pharmacology of metabotropic glutamate receptor inhibition of cyclic AMP formation in the adult rat hippocampus. Neurochem Int. 1993 Mar;22(3):277–283. doi: 10.1016/0197-0186(93)90056-b. [DOI] [PubMed] [Google Scholar]
  35. Schoepp D. D., Johnson B. G. Selective inhibition of excitatory amino acid-stimulated phosphoinositide hydrolysis in the rat hippocampus by activation of protein kinase C. Biochem Pharmacol. 1988 Nov 15;37(22):4299–4305. doi: 10.1016/0006-2952(88)90610-7. [DOI] [PubMed] [Google Scholar]
  36. Schoepp D., Bockaert J., Sladeczek F. Pharmacological and functional characteristics of metabotropic excitatory amino acid receptors. Trends Pharmacol Sci. 1990 Dec;11(12):508–515. doi: 10.1016/0165-6147(90)90052-a. [DOI] [PubMed] [Google Scholar]
  37. Shigemoto R., Nomura S., Ohishi H., Sugihara H., Nakanishi S., Mizuno N. Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain. Neurosci Lett. 1993 Nov 26;163(1):53–57. doi: 10.1016/0304-3940(93)90227-c. [DOI] [PubMed] [Google Scholar]
  38. Sladeczek F., Pin J. P., Récasens M., Bockaert J., Weiss S. Glutamate stimulates inositol phosphate formation in striatal neurones. Nature. 1985 Oct 24;317(6039):717–719. doi: 10.1038/317717a0. [DOI] [PubMed] [Google Scholar]
  39. Thompson N. T., Bonser R. W., Garland L. G. Receptor-coupled phospholipase D and its inhibition. Trends Pharmacol Sci. 1991 Nov;12(11):404–408. doi: 10.1016/0165-6147(91)90617-2. [DOI] [PubMed] [Google Scholar]
  40. Thomsen C., Boel E., Suzdak P. D. Actions of phenylglycine analogs at subtypes of the metabotropic glutamate receptor family. Eur J Pharmacol. 1994 Mar 15;267(1):77–84. doi: 10.1016/0922-4106(94)90227-5. [DOI] [PubMed] [Google Scholar]
  41. Thomsen C., Mulvihill E. R., Haldeman B., Pickering D. S., Hampson D. R., Suzdak P. D. A pharmacological characterization of the mGluR1 alpha subtype of the metabotropic glutamate receptor expressed in a cloned baby hamster kidney cell line. Brain Res. 1993 Aug 13;619(1-2):22–28. doi: 10.1016/0006-8993(93)91592-g. [DOI] [PubMed] [Google Scholar]
  42. Watkins J., Collingridge G. Phenylglycine derivatives as antagonists of metabotropic glutamate receptors. Trends Pharmacol Sci. 1994 Sep;15(9):333–342. doi: 10.1016/0165-6147(94)90028-0. [DOI] [PubMed] [Google Scholar]
  43. Winder D. G., Conn P. J. Activation of metabotropic glutamate receptors in the hippocampus increases cyclic AMP accumulation. J Neurochem. 1992 Jul;59(1):375–378. doi: 10.1111/j.1471-4159.1992.tb08914.x. [DOI] [PubMed] [Google Scholar]

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