G Protein Abnormalities in Schizophrenia

  • Naoki Nishino
  • Noboru Kitamura
  • Chang-Qing Yang
  • Hideo Yamamoto
  • Yutaka Shirai
  • Yasuo Kajimoto
  • Osamu Shirakawa
Part of the Neuromethods book series (NM, volume 31)


Since Emil Kraepelin coined the term dementia praecox, schizophrenia has been recognized as a group of illnesses of unknown etiology sharing common symptomatology with diverse clinical courses. Family, twin, and adoption studies indicate that genetic factors contribute to the etiology of schizophrenia. There has been evidence for involvement of many neurotransmitter receptor subtypes in the pathophysiology of schizophrenia. The champion of these is the dopamine (DA) receptor because DA-D2 receptors are targets of neuroleptics and have been found to be elevated in schizophrenia. The recent cloning of genes encoding five distinct DA receptor subtypes (D1-D5) and the discovery of a functional polymorphism within each gene have made it possible to investigate linkage of each DA receptor locus with genetic susceptibility to schizophrenia. To date there appears to exist no linkage between schizophrenia and the known DA receptors (Coon et al., 1993; Nöthen et al., 1994). Normal density or normal structure of a certain receptor subtypes does not always mean that the downstream partners of the receptor (G proteins, effectors, protein kinases, phosphatases) are normal.


Schizophrenic Patient Adenylyl Cyclase cAMP Production Pleckstrin Homology Domain Superior Temporal Cortex 
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.


  1. Barta, P. E, Pearlson, G. D., Powers, R. E., Richards, S. S, and Tune, L. E. (1990) Auditory hallucinations and smaller superior temporal gyral volume m schizophrenia. Am J. Psychiatry 147, 1457–1462.PubMedGoogle Scholar
  2. Bigay, J, Faurobert, E., Franco, M., and Chabre, M. (1994) Roles of lipid modifications of transducin subunits in their GDP-dependent association and membrane binding Biochemistry 33, 14,081–14,090.PubMedCrossRefGoogle Scholar
  3. Buss, J. E., Mumby, S. M., Casey, P J, Gilman, A. G., and Sefton, B M (1987) Myristoylated α-subunits of guanine nucleotide-binding regulatory proteins. Proc. Natl Acad. Sci. USA 84, 7493–7497.PubMedCrossRefGoogle Scholar
  4. Clapham, D. E. (1995) Calcium signaling. Cell 80, 259–268PubMedCrossRefGoogle Scholar
  5. Clapham, D E. (1996) The G protein nanomachine Nature (Lond ) 379, 297–299CrossRefGoogle Scholar
  6. Cleghorn, J. M, Franco, S, Szechtman, B., Kaplan, R. D., Szechtman, H, Brown, G M., Nahmias, C, and Garnett, E. S. (1992) Toward a brain map of auditory hallucinations. Am. J Psychiatry 149, 1062–1069PubMedGoogle Scholar
  7. Colin, S. F., Chang, H C., Mollner, S., Pfeuffer, T., Reed, R. R., Duman, R S, and Nestler, E. J. (1991) Chronic lithium regulates the expression of adenylate cyclase and Gi-protein α subunit m rat cerebral cortex. Proc. Natl. Acad. Sci. USA 88, 10,634–10,637PubMedCrossRefGoogle Scholar
  8. Conklin, B. R. and Bourne, H. R (1993) Structural elements of Gα-subunits that interact with Gβγ, receptors, and effectors. Cell 73, 631–641.PubMedCrossRefGoogle Scholar
  9. Coon, H., Byerley, W., Holik, J., Hoff, M., Myles-Worsley, M., Lannfelt, L., Sokoloff, P., Schwartz, J.-C, Waldo, M., Freedman, R, and Plaetke, R. (1993) Linkage analysis of schizophrenia with five dopamine receptor genes in nine pedigrees Am. J. Hum. Genet. 52, 327–334.PubMedGoogle Scholar
  10. Das, I, Essali, M. A., de Belleroche, J, and Hirsch, S. R. (1992) Inositol phospholipid turnover in platelets of schizophrenic patients Prostaglandins Leukot Essent Fatty Acids 46, 65–66.PubMedCrossRefGoogle Scholar
  11. Dhermy, D. (1991) The spectrin super-family Biol. Cell 71, 249–254PubMedGoogle Scholar
  12. Ebstein, R. P, Bennett, E. R., Hadjez, J, Silver, H., Yedgar, S., and Lerer, B. (1990) Cyclic AMP second messenger signal generation m EBV-transformed lymphoblastoid cells from schizophrenic patients J. Psychiatr Res 24, 121–127.PubMedCrossRefGoogle Scholar
  13. Essali, M. A., Das, I., de Belleroche, J, and Hirsch, S. R (1990) The platelet polyphosphoinositide system in schizophrenia, the effects of neuroleptic treatment. Biol. Psychiatry 28, 475–487PubMedCrossRefGoogle Scholar
  14. Fukuda, Y., Takao, T., Ohguro, H, Yoshizawa, T., Akino, T., and Shimonishi, Y (1990) Farnesylated γ-subunit of photoreceptor G protein indispensable for GTP-binding Nature (Lond.) 346, 658–660.CrossRefGoogle Scholar
  15. Furuichi, T, Furutama, D., Hakamata, Y., Nakai, J., Takeshima, H., and Mikoshiba, K. (1994) Multiple types of ryanodine receptor/Ca2+ release channels are differentially expressed in rabbit brain J. Neurosci. 14, 4794–4805.PubMedGoogle Scholar
  16. Garver, D. L., Johnson, C., and Kanter, D R. (1982) Schizophrenia and reduced cyclic AMP production, evidence for the role of receptor-linked events. Life Sci. 31, 1987–1992PubMedCrossRefGoogle Scholar
  17. Guiramand, J., Montmayeur, J-P., Ceraline, J., Bhatia, M., and Borrelli, E. (1995) Alternative splicing of the dopamine D2 receptor directs specificity of coupling to G proteins. J. Biol. Chem. 270, 7354–7358.PubMedCrossRefGoogle Scholar
  18. Harrison, P. J., Barton, A. J. L., McDonald, B., and Pearson, R C. A. (1991) Alzheimer’s disease: specific increases in a G protein subunit (G) mRNA in hippocampal and cortical neurons Mol.Brain Res 10, 71–81.PubMedCrossRefGoogle Scholar
  19. Haslam, R. J., Koide, H. B, and Hemmings, B. A. (1993) Pleckstrin domain homology. Nature (Lond.) 363, 309–310.CrossRefGoogle Scholar
  20. Iin, T, Herzmark, P., Nakamoto, J. M., van Dop, C, and Bourne, H. R. (1994) Rapid GDP release from G in patients with gain and loss of endocrine function. Nature 371, 164–168CrossRefGoogle Scholar
  21. Kafka, M. S, van Kammen, D. P., and Bunney, W. E, Jr. (1979) Reduced cyclic AMP production in the blood platelets from schizophrenic patients. Am J. Psychiatry 136, 685–687.PubMedGoogle Scholar
  22. Kafka, M. S and van Kammen, D. P. (1983) α-Adrenergic receptor function in schizophrenia, receptor number, cyclic adenosine monophosphate production, adenylate cyclase activity, and effect of drugs. Arch. Gen. Psychiatry 40, 264–270.PubMedGoogle Scholar
  23. Kafka, M. S., Kleinman, J E., Karson, C N., and Wyatt, R. J. (1986) Alpha-adrenergic receptors and cyclic AMP production in a group of schizophrenic patients Hillside J. Clin. Psychiatry 8, 15–24.PubMedGoogle Scholar
  24. Kaiya, H., Nishida, A., Imai, A., Nakashima, S., and Nozawa, Y. (1989) Accumulation of diacylglycerol in platelet phosphoinositide turnover in schizophrenia a biological marker of good prognosis? Biol. Psychiatry 26, 669–676PubMedCrossRefGoogle Scholar
  25. Kaiya, H, Ofuji, M., Nozaki, M, and Tsurumi, K. (1990) Platelet prostaglandin El hyposensitivity in schizophrenia decrease in cyclic AMP formation and in inhibitory effects on aggregation Psychopharmacol. Bull. 26, 381–384.PubMedGoogle Scholar
  26. Kanof, P. D, Johns, C A., Davidson, M., Siever, L. J., Coccaro, E. E, and Davis, K. L (1986) Prostaglandin receptor sensitivity in psychiatric disorders. Arch Gen. Psychiatry 43, 987–993.PubMedGoogle Scholar
  27. Kanof, P. D., Davidson, M, Johns, C A, Mohs, R. C., and Davis, K. L. (1987) Clinical correlates of platelet prostaglandin receptor subsensitivity in schizophrenia Am. J. Psychiatry 144, 1556–1560.PubMedGoogle Scholar
  28. Kanof, P. D, Coccaro, E. F, Johns, C. A., Davidson, M., Siever, L. J., and Davis, K. L. (1989) Cyclic-AMP production by polymorphonuclear leukocytes in psychiatric disorders. Biol Psychiatry 25, 413–420.PubMedCrossRefGoogle Scholar
  29. Kerwin, R W. and Beats, B. C. (1990) Increased forskolin binding in the left parahippocampal gyrus and CA1 region in post mortem schizophrenic brain determined by quantitative autoradiography. Neurosci. Lett. 118, 164–168PubMedCrossRefGoogle Scholar
  30. Kim, D., Lewis, D L., Graziadei, L., Neer, E. J., Bar-Sagi, D., and Clapham, D E.(1989) G protein βγ subunits activate the cardiac muscarinic K+-channel via phospholipase A2. Nature (Lond.) 337, 557–560.CrossRefGoogle Scholar
  31. Kitamura, N., Hashimoto, T, Nishino, N, and Tanaka, C. (1989) Inositol 1,4,5-trisphosphate binding sites in the brain: regional distribution, characterization, and alterations in brains of patients with Parkinson’s disease. J Mol. Neurosci. 1, 181–187.PubMedCrossRefGoogle Scholar
  32. Kitamura, N., Nishino, N., Hashimoto, T, et al (1997) Asymmetrical changes in the fodrin α subunit in the superior temporal cortices in schizophrenia. Biol. Psychiatry, in pressGoogle Scholar
  33. Kleuss, C, Scherubl, H., Hescheler, J., Schultz, G, and Wittig, B. (1993) Selectivity in signal transduction determined by γ subunits of heterotrimeric G protems Science 259, 832–834PubMedCrossRefGoogle Scholar
  34. Kokame, K, Fukuda, Y., Yoshizawa, T., Takao, T, and Shimonishi, Y. (1992) Lipid modification at the N terminus of photoreceptor G protein α-subunit Nature (Lond.) 359, 749–752CrossRefGoogle Scholar
  35. Krupinski, J, Coussen, F., Bakalyar, H A., Tang, W-J., Feinstein, P G., Orth, K, Slaughter, C, Reed, R. R., and Gilman, A G. (1989) Adenylyl cyclase ammo acid sequence: possible channelor transporter-like structure. Science 244, 1558–1564.PubMedCrossRefGoogle Scholar
  36. Kurachi, Y, Ito, H, Sugimoto, T, Shimizu, T, Miki, I., and Ui, M (1989) Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel Nature (Lond.) 337, 555–557.CrossRefGoogle Scholar
  37. Landis, C A, Masters, S B., Spada, A., Pace, A. M, Bourne, H. R, and Vallar, L. (1989) GTPase inhibiting mutations activate the α chain of the Gs and stimulate adenylyl cyclase in human pituitary tumors. Nature (Lond.) 340, 692–696.CrossRefGoogle Scholar
  38. Li, Y, Mortensen, R., and Neer, E J. (1994) Regulation of αo expression by the 5′-flanking region of the αo gene J.Biol Chem 269, 27,589–27,594.PubMedGoogle Scholar
  39. Lombardo, C R., Weed, S. A., Kennedy, S P., Forget, B. G., and Morrow, J S. (1994) βII-Spectrin (fodrin) and βIΣ2-spectrin (muscle) contain NH2-and COOH-terminal membrane association domains (MAD1 and MAD2). J iol. Chem 269, 29,212–29,219Google Scholar
  40. Lyons, J., Landis, C. A., Harsh, G, Vallar, L, Grunewald, K, Feichtinger, H., Duh, Q-Y, Clark, O. H, Kawasaki, E., Bourne, H R. et al (1990) Two G protein oncogenes in human endocrine tumors Science 249, 655–659.PubMedCrossRefGoogle Scholar
  41. Manji, H K (1992) G proteins implications for psychiatry Am J. Psychiatry 149, 746–760.PubMedGoogle Scholar
  42. Memo, M., Kleinman, J E, and Hanbauer, I. (1983) Coupling of dopamine D1 recognition sites with adenylate cyclase in nuclei accumbens and caudatus of schizophrenics Science 221, 1304–1307PubMedCrossRefGoogle Scholar
  43. Miric, A, Vechio, J D, and Levine, M. A. (1993) Heterogeneous mutations in the gene encodmg the α-subunit of the stimulatory G protein of adenylyl cyclase in Albright hereditary osteodystrophy. J Clin Endocnnol Metab 76, 1560–1568.CrossRefGoogle Scholar
  44. Mons, N. and Cooper, D M F (1995) Adenylate cyclase: critical foci in neuronal signaling. Trends Neurosci. 18, 536–542.PubMedCrossRefGoogle Scholar
  45. Mumby, S. M., Casey, P J, Gilman, A. G., Gutowski, S., and Sternweis, P. C. (1990) G protein g suburats contain a 20-carbon isoprenoid. Proc. Natl. Acad. Sa USA 87, 5873–5877.CrossRefGoogle Scholar
  46. Neer, E. J. (1995) Heterotrimenc G proteins: organizers of transmembrane signals Cell 80, 249–257.PubMedCrossRefGoogle Scholar
  47. Nestler, E J, Terwilliger, R Z., Walker, J. R., Sevarmo, K. A., and Duman, R. S. (1990) Chronic cocaine treatment decreases levels of the G protein subunits G and G in discrete regions of rat brain J Neurochem 55, 1079–1082.PubMedCrossRefGoogle Scholar
  48. Neubig, R R. (1994) Membrane organization in G protein mechanisms FASEB J 8, 939–946PubMedGoogle Scholar
  49. Nishino, N, Kitamura, N., Nakai, T., Hashimoto, T, and Tanaka, C. (1989) Phorbol ester binding sites in human brain characterization, regional distribution, age-correlation, and alterations in Parkinson’s disease. J. Mol. Neurosa. 1, 19–26.CrossRefGoogle Scholar
  50. Nishino, N., Kitamura, N., Hashimoto, T., Kajimoto, Y, Shirai, Y., Murakami, N., Nakai, T., Komure, O., Shirakawa, O., Mita, T., and Nakai, H. (1993) Increase in [3H]cAMP binding sites and decrease in G and G immunoreactivities in left temporal cortices from patients with schizophrenia. Brain Res. 615, 41–49PubMedCrossRefGoogle Scholar
  51. Nishizuka, Y. (1995) Protein kinase and lipid signaling for sustained cellular responses FASEB J 9, 484–496.PubMedGoogle Scholar
  52. Nöthen, M. M., Wildenauer, D, Cichon, S., Albus, M., Maier, W., Minges, J, Lichtermann, D., Bondy, B., Rietschel, M., Korner, J., Fimmers, R., and Propping, P (1994) Dopamine D2 receptor molecular variant and schizophrenia. Lancet 343, 1301–1302.PubMedCrossRefGoogle Scholar
  53. Okada, F., Crow, T. J, and Roberts, G. W. (1990) G proteins (Gi, Go) in the basal ganglia of control and schizophrenic brain J Neural Transm. (Gen. Section) 79, 227–234CrossRefGoogle Scholar
  54. Okada, F., Crow, T. J., and Roberts, G W. (1991) G proteins (Gi, Go) in the medial temporal lobe in schizophrenia; preliminary report of a neurochemical correlate of structural change. J. Neural Transm (Gen. Section) 84, 147–153CrossRefGoogle Scholar
  55. Okada, F, Tokumitsu, Y, Takahashi, N, Crow, T. J., and Roberts, G W (1994) Reduced concentrations of the α-subunit of GTP-binding protein Go in schizophrenic brain. J. Neural Transm. (Gen. Section) 95, 95–104CrossRefGoogle Scholar
  56. Pandey, G. N., Garver, D. L., Tammmga, C, Ericksen, S, Ali, S. I., and Davis, J M. (1977) Postsynaptic supersensitivity in schizophrenia Am. J. Psychiatry 134, 518–522.PubMedGoogle Scholar
  57. Petty, R G., Barta, P. E., Pearlson, G. D, McGilchrist, I. K., Lewis, R. W, Tien, A. Y, Pulver, A., Vaughn, D D., Casanova, M. F., and Powers, R E (1995) Reversal of asymmetry of the planum temporale in schizophrenia Am. J. Psychiatry 152, 715–721.PubMedGoogle Scholar
  58. Quick, M W., Simon, M I., Davidson, N., Lester, H. A., and Aragay, A. M (1994) Differential coupling of G protein a subunits to seven-helix receptors expressed in Xenopus oocytes J Biol Chem. 269, 30,164–30,172.PubMedGoogle Scholar
  59. Rotrosen, J., Miller, A D, Mandio, D., Traficante, L. J., and Gershon, S (1978) Reduced PGE1 stimulated 3H-cAMP accumulation in platelets from schizophrenics. Life Sci 23, 1989–1996.PubMedCrossRefGoogle Scholar
  60. Rostrosen, J, Miller, A. D, Mandio, D, Traficante, L J, and Gershon, S. (1980) Prostaglandins, platelets, and schizophrenia. Arch Gen. Psychiatry 37, 1047–1054Google Scholar
  61. Seeman, P., Niznik, H B., Guan, H. C., Booth, G., and Ulpian, C. (1989) Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain. Proc Natl Acad. Sci USA 86, 10,156–10,160.PubMedCrossRefGoogle Scholar
  62. Shenton, M. E., Kikinis, R., Jolesz, F. A., Pollak, S D., LeMay, M., Wible, C. G., Hokama, H., Martin, J., Metcalf, D, Coleman, M., and McCarley, R W. (1992) Abnormalities of the left temporal lobe and thought disorder in schizophrenia, a quantitative magnetic resonance imaging study. N. Engl J Med 327, 604–612.PubMedCrossRefGoogle Scholar
  63. Siman, R., Noszek, J. C, and Kegerise, C. (1989) Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage. J. Neurosa 9, 1579–1590.Google Scholar
  64. Simon, M. I., Strathmann, M. P., and Gautam, N. (1991) Diversity of G proteins in signal transduction. Science 252, 802–808PubMedCrossRefGoogle Scholar
  65. Smrcka, A. V. and Sternweis, P. C. (1993) Regulation of purified subtypes of phosphatidylinositol specific phospholipase Cβ by G protein α and βγ subunits. J. Biol. Chem. 268, 9667–9674PubMedGoogle Scholar
  66. Spiegel, A. M., Weinstein, L. S., and Shenker, A. (1993) Abnormalities in G protein-coupled signal transduction pathways in human disease. J. Clin. Invest. 92, 1119–1125.PubMedCrossRefGoogle Scholar
  67. Tang, W.-J and Gilman, A. G. (1992) Adenylyl cyclases. Cell 70, 869–872.PubMedCrossRefGoogle Scholar
  68. Terwilliger, R, Beitner-Johnson, D., Sevarino, K A, Crain, S. M., and Nestler, E. J. (1991) A general role for adaptations in G proteins and the cyclic AMP system in mediatmg the chronic actions of morphine and cocaine on neuronal function. Brain Res 548, 100–110PubMedCrossRefGoogle Scholar
  69. Wedegaertner, P B and Bourne, H. R(1994) Activation and depalmitoylation of G. Cell 77, 1063–1070PubMedCrossRefGoogle Scholar
  70. Weinstem, L S., Shenker, A, Gejman, P V., Merino, M. J, Friedman, E., and Spiegel, A M(1991) Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325, 1688–1695.CrossRefGoogle Scholar
  71. Young, L. T, Li, P P, Kish, S. J, Siu, K. P., and Warsh, J J (1991) Postmortem cerebral cortex Gs α-subunit levels are elevated in bipolar affective disorder. Brain Res 553, 323–326PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1997

Authors and Affiliations

  • Naoki Nishino
    • 1
  • Noboru Kitamura
  • Chang-Qing Yang
    • 1
  • Hideo Yamamoto
    • 1
  • Yutaka Shirai
    • 1
  • Yasuo Kajimoto
    • 1
  • Osamu Shirakawa
    • 1
  1. 1.Department of Psychiatry and NeurologyKobe University School of MedicineKobeJapan

Personalised recommendations