Abstract
Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PI signaling system of patients with affective disorders, reported in previous studies, are related to abnormalities in one or more of its components, we studied PKC, PI-PLC activity, the expression of their specific isozymes, and expression of myristoylated alanine-rich C-kinase substrate (MARCKS) in platelets obtained from 15 drug-free hospitalized patients with bipolar disorder and 15 with major depressive disorder (unipolar) and from 15 nonhospitalized normal control subjects. We observed a significant decrease in PI-PLC and PKC activity and the expression of selective PKC α, βI, βII, and PLC δ1 isozymes in membrane and cytosol fraction of platelets from bipolar but not unipolar patients. On the other hand, the level of MARCKS was significantly increased in membrane and cytosol fraction of platelets from patients with bipolar but not unipolar disorders. These results suggest that alterations in PKC, PLC, and MARCKS may be involved in the pathophysiology of bipolar illness.
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References
Aderem A . (1992): The MARCKS brothers: A family of protein kinase C substrates. Cell 71: 713–716
Aderem A . (1995): The MARCKS family of protein kinase-C substrates. Biochem Soc Trans 23: 587–591
Allen LH, Aderem A . (1995): A role for MARCKS, the alpha isozyme of protein kinase C and myosin I in zymosan phagocytosis by macrophages. J Exp Med 182: 829–840
Altman EG, Hedeker DR, Janicak PG, Peterson JL, Davis JM . (1994): The clinician-administered rating scale for mania (CARS-M): Development, reliability, and validity. Biol Psychiatry 36: 124–134
Baldassare JJ, Henderson PA, Burns D, Loomis C, Fisher GJ . (1992): Translocation of protein kinase C isozymes in thrombin-stimulated human platelets. Correlation with 1,2-diacylglycerol levels. J Biol Chem 267: 15585–15590
Berridge MJ, Irvine RF . (1989): Inositol phosphatase and cell signaling. Nature 341: 197–205
Blackshear PJ . (1993): The MARCKS family of cellular protein kinase C substrates. J Biol Chem 268: 1501–1504
Brown AS, Mallinger AG, Renbaum LC . (1993): Elevated platelet membrane phosphatidyl inositol 4–5 bisphosphate in bipolar mania. Am J Psychiatry 150: 1252–1254
Chen J, Chang S, Duncan SA, Okano HJ, Fishell G, Aderem A . (1996): Disruption of the MacMARCKS gene prevents cranial neural tube closure and results in anencephaly. Proc Natl Acad Sci USA 93: 6275–6279
Cockcroft S, Thomas GMH . (1992): Inositol-lipid-specific phospholipase C isoenzymes and their differential regulation by receptors. Biochem J 288: 1–14
Dwivedi Y, Pandey GN . (1999a): Administration of dexamethasone up-regulates protein kinase C activity and the expression of gamma and epsilon protein kinase C isozymes in the rat brain. J Neurochem 72: 380–387
Dwivedi Y, Pandey GN . (1999b): Repeated administration of dexamethasone increases phosphoinositide-specific phospholipase C activity and mRNA and protein expression of the phospholipase C beta 1 isozyme in rat brain. J Neurochem 73: 780–790
Friedman E, Hoau Yan-Wang, Levinson D, Connell TA, Singh H . (1993): Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 33: 520–525
Garcia-Sevilla JA, Walzer C, Busquets X, Escriba PV, Balant L, Guimon J . (1997): Density of guanine nucleotide-binding proteins in platelets of patients with major depression: Increased abundance of the G alpha i2 subunit and down-regulation by antidepressant drug treatment. Biol Psychiatry 42: 704–712
Glaser M, Wanaski S, Buser CA, Boguslavsky V, Rashidzada W, Morris A, Rebecchi M, Scarlata SF, Runnels LW, Prestwich GD, Chen J, Aderem A, Ahn J, McLaughlin S . (1996): Myristoylated alanine-rich C kinase substrate (MARCKS) produces reversible inhibition of phospholipase C by sequestering phosphatidylinositol 4,5-bisphosphate in lateral domains. J Biol Chem 271: 26187–26193
Goodall AR, Turner NA, Walker JH, Ball SG, Vaughan PF . (1997): Activation of protein kinase C-alpha and translocation of the myristoylated alanine-rich C-kinase substrate correlate with phorbol ester-enhanced noradrenaline release from SH-SY5Y human neuroblastoma cells. J Neurochem 68: 392–401
Grabarek J, Raychowdhury M, Ravid K, Kent KC, Newman PJ, Ware JA . (1992): Identification and functional characterization of protein kinase C isozymes in platelets and HEL cells. J Biol Chem 267: 10011–10017
Gurguis GN, Vo SP, Griffith JM, Rush AJ . (1999): Platelet alpha-2A-adrenoceptor function in major depression: Gi coupling, effects of imipramine and relationship to treatment outcome. Psychiatry Res 89: 73–95
Hall C, Monfries C, Smith P, Lim HH, Kozma R, Ahmed S, Vanniasingham V, Leung T, Lim L . (1990): Novel human brain cDNA encoding a 24,000 Mr protein n-chimaerin, related to both the regulatory domain of protein kinase C and BCR, the product of the breakpoint cluster region gene. J Mol Biol 211: 11–16
Ikonomov OC, Manji HK . (1999): Molecular mechanisms underlying mood stabilization in manic-depressive illness: The phenotype challenge. Am J Psychiatry 156: 1506–1514
Jope RS . (1999): Anti-bipolar therapy: Mechanism of action of lithium. Mol Psychiatry 4: 117–128
Jope RS, Song L, Li PP, Young LT, Kish SJ, Pacheco MA, Warsh JJ . (1996): The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain. J Neurochem 66: 2402–2409
Karege F, Bovier P, Rudolph W, Gaillard JM . (1996): Platelet phosphoinositide signaling system: An overstimulated pathway in depression. Biol Psychiatry 39: 697–702
Karege F, Bovier P, Stepanin R, Malafosse A . (1998): The effect of clinical outcome on platelet G proteins of major depressed patients. Eur Neuropsychopharmacol 8: 89–94
Kishimoto A, Mikawa K, Hashimoto K, Yasuda I, Tanaka S, Tominaga M, Kuroda T, Nishizuka Y . (1989): Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain). J Biol Chem 264: 4088–4092
Lenox RH, Manji KK . (1998): Lithium. In Schatzberg AF, Nemeroff CB (eds), American Psychiatric Press Textbook of Psychopharmacology, 2nd ed. Washington, DC, American Psychiatric Press, pp 379–429
Lenox RH, Watson DG, Patel J, Ellis J . (1992): Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 570: 333–340
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ . (1951): Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275
Manji HK, Lenox RH . (1999): Protein kinase C signaling in the brain: Molecular transduction of mood stabilization in the treatment of manic depressive illness. Biol Psychiatry 46: 1328–1351
Manji HK, Etcheberrigaray R, Chen G, Olds JL . (1993): Lithium decreases membrane-associated protein kinase C in hippocampus: Selectivity for the α isozyme. J Neurochem 61: 2302–2310
Manji HK, Potter WZ, Lenox RH . (1995): Signal transduction pathways: Molecular targets for lithium's action. Arch Gen Psychiatry 52: 531–543
Mathews R, Li PP, Young LT, Kish SJ . (1997): Increased Gαq/11 immunoreactivity in postmortem occipital cortex from platelets with bipolar affective disorder. Biol Psychiatry 41: 649–656
McLaughlin S, Aderem A . (1995): The myristoyl-electrostatic switch: A modulator of reversible protein-membrane interactions. Trends Biochem Sci 20: 272–276
McNamara RK, Hyde TM, Kleinman JE, Lenox RH . (1999): Expression of the myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP) in the prefrontal cortex and hippocampus of suicide victims. J Clin Psychiatry 60 (Suppl 2): 21–26
Mikuni M, Kusumi I, Kagaya A, Kuroda Y, Mori H, Takahashi K . (1991): Increased 5-HT2 receptor function as measured by serotonin stimulated phosphoinositide hydrolysis in platelets of depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 15: 49–61
Myat MM, Anderson S, Allen LA, Aderem A . (1997): MARCKS regulates membrane ruffling and cell spreading. Curr Biol 7: 611–614
Nishizuka Y . (1992): Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258: 607–613
Pacheco MA, Stockmeier C, Meltzer HY, Overholser JC, Dilley GE, Jope RS . (1996): Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain. Brain Res 723: 37–45
Pandey GN, Pandey SC, Davis JM . (1990): Peripheral adrenergic receptors in affective illness and schizophrenia. Pharmacol Toxicol 66 (Suppl 3): 13–36
Pandey GN, Pandey SC, Dwivedi Y, Sharma RP, Janicak PG, Davis JM . (1995): Platelet serotonin-2A receptors: A potential biological marker for suicidal behavior. Am J Psychiatry 152: 850–855
Pandey GN, Dwivedi Y, Kumari R, Janicak PG . (1998): Protein kinase C in platelets of depressed patients. Biol. Psychiatry 44: 909–911
Pandey GN, Dwivedi Y, Pandey SC, Teas SS, Conley RR, Roberts RC, Tamminga CA . (1999): Low phosphoinositide-specific phospholipase C activity and expression of phospholipase C beta1 protein in the prefrontal cortex of teenage suicide subjects. Am J Psychiatry 156: 1895–1901
Soares JC, Mallinger AG . (1996): Abnormal phosphatidylinositol (PI)-signaling in bipolar disorder. Biol Psychiatry 39: 461–464
Soares JC, Barwell M, Mallinger AG, Kupfer DJ, Frank E . (1999): Adjunctive antipsychotic use in bipolar patients: an open 6-month prospective study following an acute episode. J Affect Disord 56: 1–8
Soares JC, Chen G, Dippold CS, Wells KF, Frank E, Kuppfer DJ, Manji HK, Mallinger AG . (2000): Concurrent measures of protein kinase C and phosphoinositide in lithium treated bipolar patients and healthy individuals: A preliminary study. Psychiatry Res 95: 109–118
Wang HY, Markowitz P, Levinson D, Undie AS, Friedman E . (1999): Increased membrane-associated protein kinase C activity and translocation in blood platelets. J Psychiatr Res 33: 171–179
Wang J, Arbuzova A, Hangyas-Mihalyne G, McLaughlin S . (2001): The effector domain of myristoylated alanine-rich C kinase substrate (MARCKS) binds strongly to phosphatidylinositol 4,5-bisphosphate (PIP2). J Biol Chem 276: 5012–5019
Wang L, Watson DG, Lenox RH . (2000): Myristoylation alters retinoic acid-induced down-regulation of MARCKS in immortalized hippocampal cells. Biochem Biophys Res Commun 276: 183–188
Watson DG, Lenox RH . (1996): Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: Potentiation by muscarinic receptor activation. J Neurochem 67: 767–777
Watson DG, Wainer BH, Lenox RH . (1994): Phorbol ester and retinoic acid-induced regulation of the protein kinase C substrate MARCKS in immortalized hippocampal cells. J Neurochem 63: 1666–1674
Wilkinson SE, Hallam TJ . (1994): Protein kinase C: Is its pivotal role in cellular activation over-stated? Trends Pharmacol Sci 15: 53–57
Yamauchi E, Kiyonami R, Kanai M, Taniguchi H . (1998): The C-terminal conserved domain of MARCKS is phosphorylated in vivo by proline-directed protein kinase. Application of ion trap mass spectrometry to the determination of protein phosphorylation sites. J Biol Chem 273: 4367–4371
Young LT, Wang JF, Woods CM, Robb JC . (1999): Platelet protein kinase C alpha levels in drug-free and lithium-treated subjects with bipolar disorder. Neuropsychobiology 40: 63–66
Acknowledgements
The technical assistance of Barbara Brown and Miljana Petkovic and the help of Jim Peterson in diagnosing patients and blood collection are gratefully acknowledged. This work was supported by a grant from the National Institute of Mental Health (RO1-MH-56528 to GNP) and in part by a General Clinical Research Center Program Project from National Institute of Health (MO1RR13987 to Dr. G. Moss).
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Pandey, G., Dwivedi, Y., SridharaRao, J. et al. Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients. Neuropsychopharmacol 26, 216–228 (2002). https://doi.org/10.1016/S0893-133X(01)00327-X
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DOI: https://doi.org/10.1016/S0893-133X(01)00327-X
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