Current Psychiatry Reports

, Volume 2, Issue 6, pp 479–489 | Cite as

Post-receptor signaling pathways in the pathophysiology and treatment of mood disorders

  • Husseini K. Manji
  • Guang Chen
Article

Abstract

The molecular medicine revolution has resulted in a more complete understanding about the etiology and pathophysiology of a variety of illnesses. This remarkable progress reflects in large part the elucidation of the basic mechanisms of signal transduction, and the application of the powerful tools of molecular biology to the study of human disease. Although we have yet to identify the speci&c abnormal genes in mood disorders, recent studies have implicated signal transduction pathways, in particular the stimulatory guanine nucleotide binding protein (Gs)/cyclic AMP and protein kinase C pathways, in the pathophysiology and treatment of mood disorders. Recent studies have also shown that mood stabilizers exert neurotrophic and neuroprotective effects not only in preclinical paradigms, but also in humans. Together, these studies suggest that mood disorders may be associated with impaired neuroplasticity and cellular resiliency, &ndings that may have major implications for our understanding of mood disorders, and for the development of improved therapeutics.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Weintraub BD: Molecular Endocrinology: Basic Concepts and Clinical Correlations. New York: Raven Press; 1995.Google Scholar
  2. 2.
    Spiegel AM: G Proteins, receptors, and disease. Totowa, NJ: Humana Press; 1998.Google Scholar
  3. 3.
    Goodwin FK, Jamison KR: Manic-Depressive Illness. New York: Oxford University Press; 1990.Google Scholar
  4. 4.
    Manji HK, Potter WZ: Monoaminergic mechanisms. In Bipolar Disorder: Biological Models and their Clinical Application. Edited by Joffe RT, Young LT. New York: Marcel Dekker; 1997:1–40.Google Scholar
  5. 5.
    Schatzberg AF, Schildkraut JJ: Recent studies on norepinephrine systems in mood disorders. In Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York: Raven Press; 1995:911–920.Google Scholar
  6. 6.
    Willner P: Dopaminergic mechanisms in depression and mania. In Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York: Raven Press; 1995:921–931.Google Scholar
  7. 7.
    Maes M, Meltzer HY: The serotonin hypothesis of major depression. In Psychopharmacology: The Fourth Generation of Progrss. Edited by Bloom FE, Kupfer DJ. New York: Raven Press; 1995:933–944.Google Scholar
  8. 8.
    Garlow SJ, Musselman DL, Nemeroff CB: The neurochemistry of mood disorders clinical studies. In Neurobiology of Mental Illness. Edited by Charney DS, Nester EJ, Bunney BS. New York: Oxford University Press; 1999:348–364.Google Scholar
  9. 9.
    Janowsky DS, Overstreet DH. The role of acetylcholine mechanisms in mood disorders. In Psychopharmacology: The Fourth Generation of Progress. Edited by Bloom FE, Kupfer J. New York: Raven Press; 1995:945–956.Google Scholar
  10. 10.
    Hudson CJ, Young LT, Li PP, Warsh JJ: CNS signal transduction in the patho-physiology and pharmacotherapy of affective disorders and schizophrenia. Synapse 1993, 13:278–293.PubMedCrossRefGoogle Scholar
  11. 11.
    CL: Toward an integrated biological model of bipolar disorder. In Bipolar Disorder: Biological Models and Their Clinical Application. Edited by Young LT, Joffe RT. New York: Marcel Dekker; 1997:235–254.Google Scholar
  12. 12.
    Manji HK, Chen G, Hsiao JK, et al.: Regulation of signal transduction pathways by mood stabilizing agents: implications for the pathophysiology and treatment of bipolar affective disorder. In Bipolar Medications: Mechanisms of Action. Edited by Manji HK, Bowden CL, Belmaker RH. Washington: American Psychiatric Press; 2000a:129–177.Google Scholar
  13. 13.
    Manji HK, Chen G, Shimon H, et al.: Guanine nucleotide binding proteins in bipolar affective disorder: effects of long-term lithium treatment. Arch Gen Psych 1995a, 52:135–144.Google Scholar
  14. 14.
    Manji HK, Potter WZ, Lenox RH: Signal transduction pathways: molecular targets for lithium’s actions. Arch Gen Psych 1995b, 52:531–543.Google Scholar
  15. 15.
    Wang JF, Young LT, Li PP, Warsh JJ: Signal transduction abnormalities in bipolar disorder. In Bipolar Disorder: Biological Models and their Clinical Application. Edited by Joffe RT, Young LT. New York: Marcel Dekker; 1997:41–79.Google Scholar
  16. 16.
    Post RM, Weiss SRB, Clark M, et al.: Lithium, carbamazepine, and valproate in affective illness: biochemical and neurobiological mechanisms. In Bipolar Medications: Mechanisms of Action. Edited by Manji HK, Bowden CL, Belmaker RH. Washington: American Psychiatric Press; 2000:219–248.Google Scholar
  17. 17.
    Warsh JJ, Young LT, Li PP: Guanine nucleotide binding (G) protein disturbances in bipolar affective disorder. In Bipolar Medications: Mechanisms of Action. Edited by Manji HK, Bowden CL, Belmaker RH. Washington: American Psychiatric Press; 2000:299–329.Google Scholar
  18. 18.
    Bourne HR, Nicoll R: Molecular machines integrate coincident synaptic signals. Cell Supp 1993, 72:65–75.Google Scholar
  19. 19.
    Bhalla US, Iyengar R: Emergent properties of networks of biological signaling pathways. Science 1999, 283:381–387. This paper describes the networks that signaling proteins form, and there importance for regulating complex biologic systems.PubMedCrossRefGoogle Scholar
  20. 20.
    Weng G, Bhalla US, Iyengar R: Complexity in biological signaling systems. Science 1999, 284:92–96.PubMedCrossRefGoogle Scholar
  21. 21.
    Manji HK: G proteins: implications for psychiatry. Am J Psychiatry 1992, 149:746–760.PubMedGoogle Scholar
  22. 22.
    Milligan G, Wakelam M: G Proteins: Signal Transduction & Disease. San Diego, CA: Academic Press; 1992.Google Scholar
  23. 23.
    Weinstein LS: Alteration of G protein expression or function in pathophysiology. In G Proteins. Edited by Spiegel AM, Jones TLZ, Simonds WF, Weinstein LS. Georgetown, TX: RG Landes Company; 1994:118–128.Google Scholar
  24. 24.
    Schreiber G, Avissar S, Danon A, Belmaker RH: Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry 1991, 29:273–80.PubMedCrossRefGoogle Scholar
  25. 25.
    Young LT, Li PP, Kish SJ, et al.: Cerebral cortex Gs a protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem 1993, 61:890–898.PubMedCrossRefGoogle Scholar
  26. 26.
    Mitchell PB, Manji HK, Chen G, et al.: Increased levels of Gas in platelets of euthymic bipolar affective disorder patients. Am J Psych 1997, 154:218–223.Google Scholar
  27. 27.
    Garcia-Sevilla JA, Walzer C, Busquets X, et al.: 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 Psych 1997, 42:704–712.CrossRefGoogle Scholar
  28. 28.
    Garcia-Sevilla JA, Escriba PV, Ozaita A, et al.: Up-regulation of immunolabeled alpha2A-adrenoceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides. J Neurochem 1999, 72:282–291.PubMedCrossRefGoogle Scholar
  29. 29.
    Spleiss O, van Calker D, Scharer L, et al.: Abnormal G protein alpha(s)-and alpha(i2)-subunit mRNA expression in bipolar affective disorder. Mol Psych 1998, 3:512–520.CrossRefGoogle Scholar
  30. 30.
    Li PP, Andreopoulos S, Warsh JJ: Signal transduction abnormalities in bipolar affective disorder. In Cerbral Signal. Edited by Reith MEA. New Jersey: Humana Press; 2000:283–312.CrossRefGoogle Scholar
  31. 31.
    Wang HY, Friedman E: Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psych 1996, 40:568–575.CrossRefGoogle Scholar
  32. 32.
    Ram A, Guedj F, Cravchik A, et al.: No abnormality in the gene for the G protein stimulatory a subunit in patients with bipolar disorder. Arch Gen Psych 1997, 54:44–48.Google Scholar
  33. 33.
    Siever LJ: Role of noradrenergic mechanisms in the etiology of the affective disorders. In Psychopharmacology: The Third Generation of Progress. Edited by Meltzer HY. New York: Raven; 1987:493–504.Google Scholar
  34. 34.
    Mann JJ, Brown RP, Halper JP, et al.: Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. N Engl J Med 1985, 313:715–720.PubMedCrossRefGoogle Scholar
  35. 35.
    Ebstein RP, Lerer B, Shapira B, et al.: Cyclic AMP second-messenger signal ampli&cation in depression. Br J Psychiatry 1988, 152:665–669.PubMedGoogle Scholar
  36. 36.
    Halper JP, Brown RP, Sweeney JA, et al.: Blunted beta-adrenergic responsivity of peripheral blood mononuclear cells in endogenous depression: isoproterenol dose response studies. Arch Gen Psych 1988, 45:241–244.Google Scholar
  37. 37.
    Mork A, Geisler A, Hollund P: Effects of lithium on second messenger systems in the brain. Pharmacol Toxicol 1992, 71:4–17.PubMedCrossRefGoogle Scholar
  38. 38.
    Perez J, Tardito D, Mori S, et al.: Abnormalities of cAMP signaling in affective disorders: implications for pathophysiology and treatment. Bipolar Disord 2000, 2:27–36.PubMedCrossRefGoogle Scholar
  39. 39.
    Rahman S, Li PP, Young LT, et al.: Reduced [3H] cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder. J Neurochem 1997, 68:297–304.PubMedCrossRefGoogle Scholar
  40. 40.
    &elds A, Li PP, Kish SJ, et al.: Increased cyclic AMP-dependent protein kinase activity in postmortem brain from patients with bipolar affective disorder. J Neurochem 1999, 73:1704–1710.CrossRefGoogle Scholar
  41. 41.
    Jope RS: Anti-bipolar therapy: mechanism of action of lithium. Molecular Psychiatry 1999a, 4:117–128.CrossRefGoogle Scholar
  42. 42.
    Risby ED, Hsiao JK, Manji HK, et al.: The mechanisms of action of lithium. Arch Gen Psych 1991, 48:513–524.Google Scholar
  43. 43.
    Wang HY, Friedman E: Effects of lithium on receptor-mediated activation of G proteins in rat brain cortical membranes. Neuropharmacology 1999, 38:403–414.PubMedCrossRefGoogle Scholar
  44. 44.
    Manji HK, Lenox RH: Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psych 2000, 48:518–530.CrossRefGoogle Scholar
  45. 45.
    Jope RS: A bimodal model of the mechanism of action of lithium. Mol Psychiatry 1999b, 4:21–25.CrossRefGoogle Scholar
  46. 46.
    Chen G, Masana M, Manji HK: Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo. Bipolar Disord 2000a, in press.Google Scholar
  47. 47.
    Ozaki N, Manji HK, Luiberman V, et al.: A naturally Occurring amino acid substitution of the human serotonin (5-HT) 2A receptor influences amplitude and timing of intracellular calcium mobilization. J Neurochem 1997, 68:2186–2193.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang JF, Asghari V, Rockel C, Young LT: Cyclic AMP responsive element binding protein phosphorylation and DNA binding is decreased by chronic lithium but not valproate treatment of SH-SY5Y neuroblastoma cells. Neuroscience 1999, 91:771–776.PubMedCrossRefGoogle Scholar
  49. 49.
    Cowburn RF, Marcusson JO, Eriksson A, et al.: Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims. Brain Res 1994, 633:297–304.PubMedCrossRefGoogle Scholar
  50. 50.
    Lowther S, Crompton MR. Katona CL, Horton RW: GTP gamma S and forskolin-stimulated adenylyl cyclase activity in post-mortem brain from depressed suicides and controls. Mol Psych 1996, 1:470–477.Google Scholar
  51. 51.
    Rasenick MM, Ozawa J, Chen H: Effects of antidepressant treatments on the G protein-adenylyl cyclase axis as the possible basis of therapeutic action. In Bipolar Medications: Mechanisms of Action. Edited by HK Manji, CL Bowden, RH Belmaker. Washington: American Psychiatric Press; 2000:87–108.Google Scholar
  52. 52.
    Nestler EJ, Terwilliger RZ, Duman RS: Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 1989, 53:1644–1647.PubMedCrossRefGoogle Scholar
  53. 53.
    Popoli M, Brunello N, Perez J, Racagni G: Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs. J Neurochem 2000, 74:21–33.PubMedCrossRefGoogle Scholar
  54. 54.
    Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psych 1997, 54:597–606.Google Scholar
  55. 55.
    Duman RS, Malberg K, Nakagawa S, D’Sa C: Neuronal plasticity and survival in mood disorders. Biol Psychiatry 2000, 48:732–739.PubMedCrossRefGoogle Scholar
  56. 56.
    Dowlatshahi D, MacQueen GM, Wang JF, Young LT: Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 1998, 2352:1754–1755. This study examines the levels of the cyclic AMP responsive binding protein (CREB) in postmortem human brain. Depressed patients treated with antidepressants were demonstrated to have signi&cantly higher levels, providing support for similar observations in rodents.CrossRefGoogle Scholar
  57. 57.
    Hahn CG, Friedman E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord 1999, 1:81–86.PubMedCrossRefGoogle Scholar
  58. 58.
    Nishizuka Y: Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 1995, 9:484–496.PubMedGoogle Scholar
  59. 59.
    Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992, 258:607–614.PubMedCrossRefGoogle Scholar
  60. 60.
    Stabel S, Parker PJ: Protein kinase C. Pharmacol Ther 1991, 51:71–95.PubMedCrossRefGoogle Scholar
  61. 61.
    Newton AC: Protein kinase C: structure, function, and regulation. J Biol Chem 1995, 270:28495–28498.PubMedCrossRefGoogle Scholar
  62. 62.
    Freidman E, Hoau YW, Levinson D, et al.: Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 1993, 33:520–525.CrossRefGoogle Scholar
  63. 63.
    Pandey GN, Dwivedi Y, Pandey SC, et al.: Protein kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett 1997, 228:111–114.PubMedCrossRefGoogle Scholar
  64. 64.
    Coull MA, Lowther S, Katona CL, Horton RW: Altered brain protein kinase C in depression: a post-mortem study. Eur Neuropsychopharmacol 2000, 10:283–288.PubMedCrossRefGoogle Scholar
  65. 65.
    Manji HK, Lenox RH: Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of bipolar disorder. Biol Psych 1999, 46:1328–1351. This paper presents a hypothesis, supported by both preclinical and clinical evidence, that posits that the PKC signaling pathway plays a major role in the pathophysiology and treatment of bipolar disorder.CrossRefGoogle Scholar
  66. 66.
    Manji HK, Etcheberrigaray R, Chen G, et al.: Lithium dramatically decreases membrane-associated PKC in the hippocampus: selectivity for the alpha isozyme. J Neurochem 1993, 61:2303–2310.PubMedCrossRefGoogle Scholar
  67. 67.
    Lenox RH, Watson DGJP, Ellis J: Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res 1992, 570:333–340.PubMedCrossRefGoogle Scholar
  68. 68.
    Chen G, Manji HK, Hawver DB, et al.: Chronic sodium valproate selectively decreases protein kinase C a and e in vitro. J Neurochem 1994, 63:2361–2364.PubMedCrossRefGoogle Scholar
  69. 69.
    Watson DG, Watterson JM, Lenox RH: Sodium valproate down-regulates the myristoylated alanine-rich C kinase substrate (MARCKS) in immortalized hippocampal cells: a property of protein kinase C-mediated mood stabilizers. J Pharmacol Exp Ther 1998, 285:307–316.PubMedGoogle Scholar
  70. 70.
    Lenox RH, McNamara RK, Watson DG: A molecular target for the long-term action of lithium in the brain: a phosphoprotein substrate of protein kinase C. In Bipolar Medications: Mechanisms of Action. Edited by Manji HK, Bowden CL, Belmaker RH. Washington: American Psychiatric Press; 2000:197–218.Google Scholar
  71. 71.
    Conn PJ, Sweatt JD: Protein kinase C in the nervous system. In Protein Kinase C. Edited by Kuo JF. New York: Oxford University Press; 1994:199–235.Google Scholar
  72. 72.
    Couldwell WT, Weiss MH, DeGiorgio CM, et al.: Clinical and radiographic response in patients with recurrent malignant gliomas treated with high-dose tamoxifen. Neurosurgery 1993, 32:485–489.PubMedCrossRefGoogle Scholar
  73. 73.
    Bebchuk JM, Arfken CL, Dolan-Manji S, et al.: A preliminary investigation of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania. Arch Gen Psychiatry 2000, 57:95–97.PubMedCrossRefGoogle Scholar
  74. 74.
    Dubovsky S, Murphy J, Christiano J, et al.: The calcium second messenger system in bipolar disorders: Data supporting new research directions. J Neuropsych 1992, 4:3–14.Google Scholar
  75. 75.
    Emamghoreishi M, Schlichter L, Li PP, et al.: High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder. Am J Psychiatry 1997, 154:976–82.PubMedGoogle Scholar
  76. 76.
    Hough C, Lu SJ, Davis CL, et al.: Elevated basal and thapsigargin stimulated intracellular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay. Biol Psychiatry 1999, 46:247–255.PubMedCrossRefGoogle Scholar
  77. 77.
    Magnier C, Corvazier E, Aumont MC, et al.: Relationship between Rap1 protein phosphorylation and regulation of Ca2+ transport in platelets: a new approach. Biochem J 1995, 310:4694–75.Google Scholar
  78. 78.
    Drevets WC, Gadde KM, Krishnan KRR: Neuroimaging studies of mood disorders. In Neurobiology of Mental Illness. Edited by Charney DS, Nestler EJ, Bunney BS. New York: Oxford University Press; 1999:394–418.Google Scholar
  79. 79.
    Manji HK, Moore GJ, Rajkowska G, Chen G: Neuroplasticity and cellular resilience in mood disorders. Millennium Article. Mol Psych 2000b, in press.Google Scholar
  80. 80.
    Rajkowska G: Histopathology of the prefrontal cortex in depression: what does it tell us about dysfunctional monoaminergic circuits. Prog Brain Res 2000, 126:397–412.PubMedCrossRefGoogle Scholar
  81. 81.
    Post RM, Weiss SRB: Neurobiological models of recurrence in mood disorder. In Neurobiology of Mental Illness. Edited by Charney DS, Nester EJ, Bunney BS. New York: Oxford University Press; 1999:365–384.Google Scholar
  82. 82.
    Manji HK, Moore GJ, Chen G: Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psych 1999, 46:929–940.CrossRefGoogle Scholar
  83. 83.
    Chen G, Zeng WZ, Jiang L, et al.: The mood stabilizing agents lithium and valproate robustly increase the expression of the neuroprotective protein bcl-2 in the CNS. J Neurochem 1999b, 72:879–882. This paper describes a series of mRNA RT-PCR studies which led to a hitherto completely unexpected target for the actions of chronic lithium and valproate, the major cytoprotective protein, bcl-2.CrossRefGoogle Scholar
  84. 84.
    Chen RW, Chuang DM: Long term lithium treatment suppresses p53 and Bax expression but increases bcl-2 expression. J Biol Chem 1999, 274:6039–6042.PubMedCrossRefGoogle Scholar
  85. 85.
    Nonaka S, Chuang DM: Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport 1998, 9:2081–2084.PubMedCrossRefGoogle Scholar
  86. 86.
    Chen G, Rajkowska G, Du F, et al.: Enhancement of Hippocampal Neurogenesis by Lithium. J Neurochem 2000b, 75:1729–1734. oThis study utilizes bromodeoxyuridine (BrdU), a thymidine analog that labels the DNA of dividing cells, to demonstrate that chronic lithium enhances neurogenesis in the adult mammalian neurogenesis.CrossRefGoogle Scholar
  87. 87.
    Moore GJ, Bebchuk JM, Hasanat K, et al.: Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2′s neurotrophic effects? Biol Psych 2000a, 48:1–8.CrossRefGoogle Scholar
  88. 88.
    Moore GJ, Wilds IB, Bebchuk JM, et al.: Lithium increases gray matter in bipolar disorder. Lancet 2000b, 356:1241–1242. This study utilized quantitative three-dimensional MRI in a longitudinal study of bipolar disorder subjects, to investigate putative neurotrophic effects of lithium. This study revealed the extraordinary &nding that lithium produces small but signi&cant increases in gray matter volumes in humans.CrossRefGoogle Scholar
  89. 89.
    Nestler EJ: Antidepressant treatments in the 21st century. Biol Psych 1998, 44:526–533.CrossRefGoogle Scholar
  90. 90.
    Guo Z, Zhou D, Schultz PG: Designing small-molecule switches for protein-protein interactions. Science 2000, 288:2042–2045. This paper described the recent progress that has been made in developing chemical compounds to regulate signaling pathways via protein:protein interactions. The advances have considerable potential for the development of novel signal transduction modi&ers for the treatment of human diseases.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2000

Authors and Affiliations

  • Husseini K. Manji
    • 1
  • Guang Chen
    • 1
  1. 1.Laboratory of Molecular PathophysiologyNational Institute of Mental HealthBethesdaUSA

Personalised recommendations