The Role of G Proteins in the Pathophysiology and Treatment of Affective Disorders

  • Hiroki Ozawa
  • Naohiko Takahata
Conference paper


Guanosine triphosphate (GTP)-binding proteins (G proteins) have been thought of as modulators that multiply signal information from receptors to effectors. G proteins related to membrane signaling have a heterotrimetric structure (α, β, and γ), and the α subunit has a GTP-binding site involved in GTPase activity hydrolyzing GTP to guanosine diphosphate (GDP). Therefore, the G proteins comprise a unique family of protein molecules implicated in the mechanisms switching signal transduction on and off (Simon et al. 1991). Manic-depressive illness is characterized by two phases, the manic and the depressive states, and generally is considered to be in remission in the period between episodes. From its clinical characteristics, it is conceivable that there is some difficulty in emotional adjustment involving the switching mechanisms that accelerate or diminish neurotransmission in the brain. Hence, one might assume that there is a close relationship between G protein as the protein molecule in the on-off signal switching and manic-depressive illness (Fig. 1). Since the amine hypothesis of manic-depressive illness was proposed, various hypotheses concerning the pathophysiology of this disorder have been discussed, along with the complexity of interactions among multiple neural trans-mission systems, which contrasts with the increase or decrease in single neurotransmitters such as occurs with noradrenaline and serotonin. One of the neurological bases of signal interaction is that different receptors are coupled with the same G protein.


Affective Disorder Adenylyl Cyclase Adenylyl Cyclase Activity Bipolar Affective Disorder Guanosine Triphosphate 
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  1. Avissar S, Schreiber G (1992) The involvement of guanine nucleotide binding proteins in the pathogenesis and treatment of affective disorders. Biol Psychiatr 31: 435–459CrossRefGoogle Scholar
  2. Belmaker RH, Bersudsky Y, Benjamin J, Agam G, Levine J, Kofman O (1995) Ma-nipulation of inositol-linked second messenger systems as a therapeutic strategy in psychiatry. Adv Biochem Psychopharmacol 49: 67–84PubMedGoogle Scholar
  3. Cheung J, Rasenick MM (1995) Chronic antidepressant treatment facilitates G protein activation without altering G protein content. J Pharmacol Exp Ther 275: 509–517Google Scholar
  4. Cowburn RF, Marcusson JO, Eriksson A, Wiehanger B, ONeill C (1994) Adenylyl cyclase activity and G-protein subunit levels in postmortem frontal cortex of suicide victims. Brain Res 633: 297–304PubMedCrossRefGoogle Scholar
  5. De Montis GM, Devoto P, Gessa GL (1990) Selective adenylyl cyclase increase in the limbic area of long–term imipramine-treated rats. Eur J Pharmacol 180:169–174PubMedCrossRefGoogle Scholar
  6. Dibner MD, Molinoff PB (1979) Agonist-induced changes in beta-adrenergic receptor density and receptor mediated responsiveness in slices of rat cerebral cortex. J Pharmacol Exp Ther 210: 433–439PubMedGoogle Scholar
  7. Duman RS, Strada SJ, Enna SJ (1985) Effect of imipramine and adrenocorticotropin administration on the rat brain norepinephrine-coupled cyclic nucleotide generating system: alterations in alpha and beta adrenergic components. J Pharmacol Exp Ther 234: 409–414PubMedGoogle Scholar
  8. Hancock A A, Marsh CL (1984) Selective down-regulation of high agonist affinity beta adrenergic receptors following chronic desipramine treatment. Fed Proc 43: 873Google Scholar
  9. Horowski R, Sastre-Y-Hernandez M (1985) Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients. Global evalua¬tion of the preliminary reports. Curr Ther Res 38: 23–29Google Scholar
  10. 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: 2401–2409Google Scholar
  11. Kamada H, Ozawa H, Saito T, Hatta S, Takahata N (1997) Dimeric tubulin-stimulated adenylyl cyclase activity is augmented after long–term amitriptyline treatment. Life Sei 60: 57–66CrossRefGoogle Scholar
  12. Kornhuber J, Konradi C, Mack-Burkhardt F, Riederer P, Heinsen H, Beckmann H (1989a) Ontogenesis of monoamine oxidase-A and -B in the human brain frontal cortex. Brain Res 499: 81–86PubMedCrossRefGoogle Scholar
  13. Kornhuber J, Retz W, Riederer P (1989b) Effect of antemortem and postmortem factors on [3H]glutamate binding in the human brain. Life Sei 45: 312–317CrossRefGoogle Scholar
  14. Lesch KP, Aulakh CS, Tolliver TJ, Hill JL, Murphy DL (1991) Regulation of G proteins by chronic antidepressant drug treatment in rat brain: tricyclics but not clorgyline increase Goa subunits. Eur J Pharmacol 207: 361–364PubMedCrossRefGoogle Scholar
  15. Maeda H, Ozawa H, Amemiya N, Kaneta K, Saito T, Takahata N (1996) Effects Of forskolin administration on behavioral response to forced swimming in the rat. Neurosci Abst 22: 374Google Scholar
  16. McLaughlin M, Ross BM, Milligan G, McCulloch J, Knowler JT (1991) Robustness of G proteins in Alzheimer’s disease: an immunoblot study. J Neurochem 57: 9–14PubMedCrossRefGoogle Scholar
  17. Menkes DB, Rasenick MM, Wheeler M, Bitensky MW (1983) Guanosine triphosphate activation of brain adenylyl cyclase: Enhancement by long-term antidepressant treat-ment. Science 129: 65–67Google Scholar
  18. Mishra R, Janowsky A, Sulser F (1980) Action of mianserin and zimelidine on the norepinephrine receptor coupled adenylyl cyclase system in brain: subsensitivity without reduction in beta-adrenergic receptor binding. Neuropharmacology 19: 983–987PubMedCrossRefGoogle Scholar
  19. Newman ME, Lerer B (1989) Post-receptor increases in adenylyl cyclase activity after chronic antidepressant treatment: relationship to receptor desensitization. Eur J Pharmacol 162: 345–352PubMedCrossRefGoogle Scholar
  20. O’Donnell JM, Frazer A (1985) Effects of clenbuterol and antidepressant drugs on beta adrenergic receptor N-protein coupling in cerebral cortex of the rat. J Pharmacol Exp Ther 234: 30–36Google Scholar
  21. Okada F, Tokumitsu Y, Ui M (1986) Desensitization of beta-adrenergic receptor- coupled adenylyl cyclase in cerebral cortex after in vivo treatment of rats with desipramine. J Neurochem 47: 454–459PubMedCrossRefGoogle Scholar
  22. Ozawa H, Rasenick MM (1989) Coupling of the stimulatory GTP-binding protein, Gs, to rat synaptic membrane adenylate cyclase is enhanced subsequent to chronic antidepressant treatment. Mol Pharmcol 36: 803–808Google Scholar
  23. Ozawa H, Rasenick MM (1991) Chronic electroconvulsive treatment augments cou¬pling of the GTP-binding protein Gs to the catalytic moiety of adenylyl cyclase in a manner similar to that seen with chronic antidepressant drugs. J Neurochem 56: 330–338PubMedCrossRefGoogle Scholar
  24. Ozawa H, Gsell W, Froelich L, Beckmann H, Riederer P (1993) Imbalance of the Gs and Gi/o function in post-mortem human brain of depressed patients. J Neural Transm [GenSect]94: 63–69Google Scholar
  25. Ozawa H, Katamura Y, Hatta S, Amemiya N, Saito T, Ohshika H, Takahata N (1994) Antidepressants directly influence in situ binding of guanine nucleotide in synaptic membrane. Life Sci 54: 925–932PubMedCrossRefGoogle Scholar
  26. Rasenick MM, Hughes JM, Wang N (1988) Guanosine-5-o-thiodiphosphate functions as a partial agonist for the receptor-independent stimulation of neural adenylate cyclase. Brain Res 488: 105–113CrossRefGoogle Scholar
  27. Seeman KB (1987) Forskolin and adenylyl cyclase. ISI Atlas Pharmacol 1: 250–253Google Scholar
  28. Simon M, Strathman M, Gautam N (1991) Diversity of G proteins in signal transduc¬tion. Science 252: 802–808PubMedCrossRefGoogle Scholar
  29. Tiong AHK, Richardson JS (1990) Beta-adrenoceptor and post-receptor components show different rates of desensitization to desipramine. Eur J Pharmacol 188: 411–415PubMedCrossRefGoogle Scholar
  30. Wachtel H (1989) Dysbalance of neuronal second messenger function in aetiology of affective disorders; a pathophysiological concept hypothesizing defects beyond first messenger receptors. J Neural Transm 75: 21–29PubMedCrossRefGoogle Scholar
  31. Wachtel H (1990) The second-messenger dysbalance hypothesis of affective disorders. Pharmacopsychiatry 23: 27–32PubMedCrossRefGoogle Scholar
  32. Wachtel H, Loshmann PA (1986) Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressive activity: interaction with rolipram. Psychopharmacology 90: 430–435PubMedCrossRefGoogle Scholar
  33. Woon CW, Soparkar S, Heasley L, Johnson GL (1989) Expression of a Gas/Gai chimera that constitutively activates cAMP synthesis. J Biol Chem 264: 5687–5693PubMedGoogle Scholar
  34. Yamamoto H, Tomita U, Mikuni M, Kobayashi I, Kagaya A, Katada T, Ui M, Takahashi K (1992) Direct activation of purified Go-type GTP binding protein by tricyclic antidepressants. Neurosci Lett 139: 194–196PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1998

Authors and Affiliations

  • Hiroki Ozawa
    • 1
  • Naohiko Takahata
    • 1
  1. 1.Department of Neuropsychiatry, School of MedicineSapporo Medical UniversitySapporo, Hokkaido 060Japan

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