Hormonal Regulation of Phospholipid Metabolism via G-proteins II: PLA2 and Inhibitory Regulation of PLC

  • D. Corda
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 108 / 2)


Lipid derivatives play a major role as second messengers. A large body of evidence has accumulated on the mechanisms leading to their formation and on their role in cell regulation (reviewed in Dennis et al. 1991). They are formed by the action of different phospholipases (A2, C, D) acting on membrane phospholipids. Of particular physiological relevance has been the elucidation of the hormonal regulation of these enzymes. A large number of receptors for hormones and neurotransmitters are coupled to cellular phospholipases and regulate the cytosolic levels of second messengers such as Ca2+, diacylglycerol, inositol trisphosphate, and arachidonic acid. The activation of phospholipases can be indirectly induced by a receptormediated increase in cytosolic Ca2+, or it can be due to the activation of a heterotrimeric GTP-binding (G) protein directly coupled to the enzyme.


Arachidonic Acid Adenylyl Cyclase Pertussis Toxin Thyroid Cell PLA2 Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alonso T, Morgan RO, Marvizon JC, Zarbl H, Santos E (1988) Malignant transformation by ras and other oncogenes produces common alterations in inositol phospholipid signaling pathways. Proc Natl Acad Sci USA 85:4271–4275.PubMedCrossRefGoogle Scholar
  2. Alonso T, Santos E (1990) Increased intracellular glycerophosphoinositol is a biochemical marker for transformation by membrane-associated and cytoplasmic oncogenes. Biochem Biophys Res Comm 171:14–19.PubMedCrossRefGoogle Scholar
  3. Alonso T, Srivastava S, Santos E (1990) Alterations of G-protein coupling function in phosphoinositide signaling pathways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes. Mol Cell Biol 10:3117–3124.PubMedGoogle Scholar
  4. Axelrod J, Burch RM, Jelsema CL (1988) Receptor-mediated activation of phos-pholipase A2 via GTP-binding proteins: arachidonic acid and its metabolites as second messengers. Trends Neurosci 11:117–123.PubMedCrossRefGoogle Scholar
  5. Axelrod J (1990) Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem Soc Trans 18:503–507.PubMedGoogle Scholar
  6. Bar-Sagi D, Feramisco JR (1986) Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 233:1061–1068.PubMedCrossRefGoogle Scholar
  7. Béréziat G, Etienne J, Kokkinidis M, Olivier JL, Pernas ? (1990) New trends in mammalian non-pancreatic phospholipase A2 research. J Lipid Mediat 2:159–172.PubMedGoogle Scholar
  8. Bizzarri C, Di Girolamo M, D’Orazio MC, Corda D (1990) Evidence that a guanine nucleotide-binding protein linked to a muscarinic receptor inhibits directly phospholipase C. Proc Natl Acad Sci USA 87:4889–4893.PubMedCrossRefGoogle Scholar
  9. Bokach GM, Gilman AG (1984) Inhibition of receptor-mediated release of arachidonic acid by pertussis toxin. Cell 39:301–308.CrossRefGoogle Scholar
  10. Boyer JL, Waldo GL, Evans T, Northup JK, Downes CP, Harden TK (1989) Modification of AIF4 -and receptor-stimulated phospholipase C activity by G-protein βγ subunits. J Biol Chem 264:13917–13922.PubMedGoogle Scholar
  11. Brown AM (1991) A cellular logic for G protein-coupled ion channel pathways. Faseb J 5:2175–2179.PubMedGoogle Scholar
  12. Burch RM, Luini A, Axelrod J (1986) Phospholipase A2 and phospholipase C are activated by distinct GTP-binding proteins in response to α1-adrenergic stimulation in FRTL5 thyroid cells. Proc Natl Acad Sci USA 83:7201–7205.PubMedCrossRefGoogle Scholar
  13. Burch RM, Jelsema C, Axelrod J (1988) Cholera toxin and pertussis toxin stimulate prostaglandin E2 synthesis in a murine macrophage cell line. J Pharmacol Exp Ther 244:765–773.PubMedGoogle Scholar
  14. Burch RM (1989) G Protein regulation of phospholipase A2. Mol Neurobiol 3:155–171.PubMedCrossRefGoogle Scholar
  15. Burch RM (1990) G protein regulation of phospholipase A2: partial reconstitution of the system in cells. In: Mukherjee AB (ed) Biochemistry, molecular biology, and physiology of phospholipase A2 and its regulatory factors. Plenum Press. New York and London, pp 185–195.CrossRefGoogle Scholar
  16. Burgoyne RD, Morgan A (1990) The control of free arachidonic acid levels. Trends Biochem Sci 15:365–366.PubMedCrossRefGoogle Scholar
  17. Cantiello HF, Patenaude CR, Codina J, Birnbaumer L, Ausiello DA (1990) Gαi-3 regulates epithelial Na+ channels by activation of phospholipase A2 and lipoxygenase pathways. J Biol Chem 265:21624–21628.PubMedGoogle Scholar
  18. Channon JY, Leslie CC (1990) A calcium-dependent mechanism for associating a soluble arachidonoyl-hydrolyzing phospholipase A2 with membrane in the macrophage cell line RAW 264.7. J Biol Chem 265:5409–5413.PubMedGoogle Scholar
  19. Clark JD, Milona N, Knopf JL (1990) Purification of a 110-kilodalton cytosolic phospholipase A2 from the human monocytic cell line U937. Proc Natl Acad Sci USA 87:7708–7712.PubMedCrossRefGoogle Scholar
  20. Clark JD, Lin LL, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, Milona N, Knopf JL (1991) A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+ dependent translocation domain with homology to PKC and GAP. Cell 65:1043–1051.PubMedCrossRefGoogle Scholar
  21. Cockcroft S, Nielson CP, Stutchfield J (1991) Is phospholipase A2 activation regulated by G-proteins? Biochem Soc Trans 19:333–336.PubMedGoogle Scholar
  22. Colletta G, Corda D, Schettini G, Cirafici AM, Kohn LD, Cosinglio E (1988) Adenylate cyclase activity of v-ras-k transformed rat epithelial thyroid cells. FEBS Lett 228:37–41.PubMedCrossRefGoogle Scholar
  23. Corda D, Kohn LD (1986) Role of pertussis toxin sensitive G proteins in the alphal adrenergic receptor but not in the thyrotropin receptor mediated activation of membrane phospholipases and iodide fluxes in FRTL-5 thyroid cells. Biochem Biophys Res Comm 141:1000–1006.PubMedCrossRefGoogle Scholar
  24. Corda D, Bizzarri C, Di Girolamo M, Valitutti S, Luini A (1989) G protein-linked receptors in the thyroid. Adv Exp Med Biol 261:245–269.PubMedGoogle Scholar
  25. Delahunty TM, Cronin MJ, Linden J (1988) Regulation of GH3-cell function via adenosine A1 receptors. Biochem J 255:69–77.PubMedGoogle Scholar
  26. Davidson FF, Dennis EA (1990) Evolutionary relationships and implications for the regulation of phospholipase A2 from snake venom to human secreted forms. J Mol Evol 31:228–238.PubMedCrossRefGoogle Scholar
  27. Dennis EA, Rhee SG, Billah MM, Hannun YA (1991) Role of phospholipases in generating lipid second messengers in signal transduction. FASEB J 5:2068–2077.PubMedGoogle Scholar
  28. Di Girolamo M, D’Arcangelo D, Bizzarri C, Corda D (1991) Muscarinic regulation of phospholipase A2 and iodide fluxes in FRTL-5 thyroid cells. Acta Endocrinol 125:192–200.PubMedGoogle Scholar
  29. Di Girolamo M, D’Arcangelo D, Cacciamani T, Gierschik P, Corda D (1992) K-ras transformation greatly increases the toxin-dependent ADP-ribosylation of GTP binding proteins in thyroid cells. Involvement of an inhibitor of the ADP-ribosylation reaction. J Biol Chem 267:17397–17403.PubMedGoogle Scholar
  30. Doroshenko P (1991) Second messengers mediating activation of chloride current by intracellular GTPγS in bovine chromaffin cells. J Physiol 436:725–738.PubMedGoogle Scholar
  31. Enjalbert A, Sladeczek F, Guillon G, Bertrand P, Shu C, Epelbaum J, Garcia-Sainz A, Jard S, Lombard C, Kordon C, Bockaert J (1986) Angiotensin II and dopamine modulate both cAMP and inositol phosphate productions in anterior pituitary cells. Involvement in prolactin secretion. J Biol Chem 261:4071–4075.PubMedGoogle Scholar
  32. Enjalbert A, Guillon G, Mouillac B, Audinot V, Rasolonjanahary R, Kordon C, Bockaert J (1990) Dual mechanisms of inhibition by dopamine of basal and thyrotropin-releasing hormone-stimulated inositol phosphate production in anterior pituitary cells. Evidence for an inhibition not mediated by voltage-dependent Ca2+ channels. J Biol Chem 265:18816–18822.PubMedGoogle Scholar
  33. Fain JN (1990) Regulation of phosphoinositide-specific phospholipase C. Biochim Biophys Acta 1053:81–88.PubMedCrossRefGoogle Scholar
  34. Godfrey PP, Watson SP (1988) Fluoride inhibits agonist induced formation of inositol phospates in rat cortex. Biochem Biophys Res Comm 155:664–669.PubMedCrossRefGoogle Scholar
  35. Gronich JH, Bonventre JV, Nemenoff RA (1990) Purification of a high-molecular-mass-form of phospholipase A2 from rat kidney activated at physiological calcium concentrations. Biochem J 271:37–43.PubMedGoogle Scholar
  36. Guillon G, Mouillac B, Savage AL (1992) Modulation of hormone-sensitive phospholipase C. Cell Signal 4:11–23.PubMedCrossRefGoogle Scholar
  37. Gupta SK, Diez E, Heasley LE, Osawa S, Johnson GL (1990) A G protein mutant that inhibits thrombin and purinergic receptor activation of phospholipase A2. Science 249:662–666.PubMedCrossRefGoogle Scholar
  38. Horn VJ, Baum BJ, Ambudkar IS (1990) Attenuation of inositol trisphosphate generation and cytosolic Ca2+ elevation in dispersed rat parotid acini stimulated simultaneously at muscarinic and α1-adrenergic receptors. Biochem Biophys Res Comm 166:967–972.PubMedCrossRefGoogle Scholar
  39. Huang NN, Wang DJ, Gonzalez F, Heppel LA (1991) Multiple signal transduction pathways lead to extracellular ATP-stimulated mitogenesis in mammalian cells. II. A pathway involving arachidonic acid release, prostaglandin synthesis, and cyclic AMP accumulation. J Cell Physiol 146:483–494.PubMedCrossRefGoogle Scholar
  40. Jelsema CL (1987) Light activation of phospholipase A2 in rod outer segments of bovine retina and its modulation by GTP-binding proteins. J Biol Chem 262:163–168.PubMedGoogle Scholar
  41. Jelsema CL, Axelrod J (1987) Stimulation of phospholipase A2 activity in bovine rod outer segments by the βγ subunits of transducin and its inhibition by the α subunit. Proc Natl Acad Sci USA 84:3623–3627.PubMedCrossRefGoogle Scholar
  42. Jelsema CL, Burch RM, Jaken S, Ma AD, Axelrod J (1989) Modulation of phospholipase A2 activity in rod outer segments of bovine retina by G protein subunits, guanine nucleotides, protein kinases, and calpactin. In Redburn DA, Pasantes-Morales H (eds) Extracellular and intracellular second messengers in the vertebrate retina, vol 49, Neurology and neurobiology, Alan R. Liss New York, pp 25–46.Google Scholar
  43. Kast R, Fürstenberger G, Marks F (1991) Activation of a keratinocyte phospholipase A2 by bradykinin and 4β-phorbol 12-myristate 13-acetate. Eur J Biochem 202:941–950.PubMedCrossRefGoogle Scholar
  44. Kim D, Lewis DL, Graziadei L, Neer EJ, Bar-Sagi D, Clapham DE (1989) G-protein βγ-subunits activate the cardiac muscarinic K+-channel via phospholipase A2. Nature 337:557–560.PubMedCrossRefGoogle Scholar
  45. Kramer RM, Roberts EF, Marietta J, Putnam JE (1991) The Ca-sensitive cytosolic phospholipase A2 is a 100-kDa protein in human monoblast U937 cells. J Biol Chem 266:5268–5272.PubMedGoogle Scholar
  46. Kurachi Y, Ito H, Sugimoto T, Shimizu T, Miki I, Ui M (1989) Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel. Nature 337:555–557.PubMedCrossRefGoogle Scholar
  47. Leslie CC, Voelker DR, Channon JY, Wall MM, Zelarney PT (1988) Properties and purification of an arachidonoyl-hydrolyzing phospholipase A2 from a macrophage cell line, RAW 264.7. Biochim Biophys Acta 963:476–492.PubMedGoogle Scholar
  48. Limor R, Schvartz I, Hazum E, Ayalon D, Naor Z (1989) Effect of guanine nucleotides on phospholipase C activity in permeabilized pituitary cells: possible involvement of an inhibitory GTP-binding protein. Biochem Biophys Res Comm 159:209–215.PubMedCrossRefGoogle Scholar
  49. Linden J, Delahunty TM (1989) Receptors that inhibit phosphoinositide breakdown. Trends Pharmacol Sci 10:114–120.PubMedCrossRefGoogle Scholar
  50. Litosch I (1989) Guanine nucleotides mediate stimulatory and inhibitory effects on cerebral-cortical membrane phospholipase C activity. Biochem J 261:245–251.PubMedGoogle Scholar
  51. Lowndes JM, Gupta SK, Osawa S, Johnson GL (1991) GTPase-deficient Gαi2 oncogene gip2 inhibits adenylyl cyclase and attenuates receptor-stimulated phospholipase A2 activity. J Biol Chem 266:14193–14197.PubMedGoogle Scholar
  52. Misawa H, Ueda H, Satoh M (1990) κ-Opioid agonist inhibits phospholipase C, possibly via an inhibition of G-protein activity. Neurosci Lett 112:324–327.PubMedCrossRefGoogle Scholar
  53. Moriarty TM, Gillo B, Carty DJ, Premont RT, Landau EM, Iyengar R (1988) βγ Subunits of GTP-binding proteins inhibit muscarinic receptor stimulation of phospholipase C. Proc Natl Acad Sci USA 85:8865–8869.PubMedCrossRefGoogle Scholar
  54. Nakahata N, Abe MT, Matsuoka I, Ono T, Nakanishi H (1991) Adenosine inhibits histamine-induced phosphoinositide hydrolysis mediated via pertussis toxinsensitive G-protein in human astrocytoma cells. J Neurochem 57:963–969.PubMedCrossRefGoogle Scholar
  55. Nakashima S, Nagata KI, Ueeda K, Nozawa Y (1988) Stimulation of arachidonic acid release by guanine nucleotide in saponin-permeabilized neutrophils: evidence for involvement of GTP-binding protein in phospholipase A2 activation. Arch Biochem Biophys 261:375–383.PubMedCrossRefGoogle Scholar
  56. Narasimhan V, Holowka D, Baird B (1990) A guanine nucleotide-binding protein participates in IgE receptor-mediated activation of endogenous and reconstituted phospholipase A2 in a permeabilized cell system. J Biol Chem 264:1459–1464.Google Scholar
  57. Okabe K, Yatani A, Evans T, Ho YK, Codina J, Birnbaumer L, Brown AM (1990) βγ Dimers of G proteins inhibit atrial muscarinic K+ channels. J Biol Chem 265:12854–12858.PubMedGoogle Scholar
  58. Price BD, Morris JDH, Marshall CJ, Hall A (1989) Stimulation of phosphatidylcholine hydrolysis, diacylglycerol release, and arachidonic acid production by oncogenic ras is a consequence of protein kinase C activation. J Biol Chem 264:16638–16643.PubMedGoogle Scholar
  59. Rehfeldt W, Hass R, Goppelt-Struebe M (1991) Characterization of phospholipase A2 in monocytic cell lines. Functional and biochemical aspects of membrane association. Biochem J 276:631–636.PubMedGoogle Scholar
  60. Rhee SG, Suh P-G, Ryu S-H, Lee SY (1989) Studies of inositol phospholipid-specific phospholipase C. Science 244:546–550.PubMedCrossRefGoogle Scholar
  61. Rubin RP, Withiam-Leitch M, Laychock SG (1991) Modulation of phospholipase A2 activity in zymogen granule membranes by GTPγ(S); evidence for GTP-binding protein regulation. Biochem Biophys Res Comm 177:22–26.PubMedCrossRefGoogle Scholar
  62. Sharp JD, White DL, Chiou XG, Goodson T, Gamboa GC, McClure D, Burgett S, Hoskins J, Skatrud PL, Sprtsman JR, Becker GW, Kang LH, Roberts EF, Kramer RM (1991) Molecular cloning and expression of human Ca2+-sensitive cytosolic phospholipase A2. J Biol Chem 266:14850–14853.PubMedGoogle Scholar
  63. Teitelbaum I (1990) The epidermal growth factor receptor is coupled to a phospholipase A2-specific pertussis toxin-inhibitable guanine nucleotide-binding regulatory protein in cultured rat inner medullary collecting tubule cells. J Biol Chem 265:4218–4222.PubMedGoogle Scholar
  64. Tremblay NM, Nicholson D, Potier M, Weech PK (1992) Cytosolic phospholipase A2 from U937 cells: size of the functional enzyme by radiation inactivation. Biochem Biophys Res Comm 183:121–127.PubMedCrossRefGoogle Scholar
  65. Valitutti S, Cucchi P, Colletta G, Di Filippo C, Corda D (1991) Transformation by the K-ras oncogene correlates with increases in phospholipase A2 activity, glycerophosphoinositol production and phosphoinositide synthesis in thyroid cells. Cell Signal 3:321–332.PubMedCrossRefGoogle Scholar
  66. Vallar L, Vicentini LM, Meldolesi J (1988) Inhibition of inositol phosphate production is a late, Ca2+-dependent effect of D2 dopaminergic receptor activation in rat lactotroph cells. J Biol Chem 263:10127–10134.PubMedGoogle Scholar
  67. Yatani A, Mattera R, Codina J, Graf R, Okabe K, Padrell E, Iyengar R, Brown AM, Birnbaumer L (1988) The G protein-gated atrial K+ channel is stimulated by three distinct Giα-subunits. Nature 336:680–682.PubMedCrossRefGoogle Scholar
  68. Yatani A, Okabe K, Polakis P, Halenbeck R, McCormick F, Brown AM (1990) ras p21 and GAP inhibit coupling of muscarinic receptor to atrial K+ channels. Cell 61:769–776.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • D. Corda

There are no affiliations available

Personalised recommendations