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Second messenger/signal transduction pathways in major mood disorders: moving from membrane to mechanism of action, part II: bipolar disorder

Published online by Cambridge University Press:  11 March 2013

Mark J. Niciu ,
Dawn F. Ionescu ,
Daniel C. Mathews ,
Erica M. Richards  and
Carlos A. Zarate Jr.
Mark J. Niciu*
Affiliation:
National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, Bethesda, Maryland, USA
Dawn F. Ionescu
Affiliation:
National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, Bethesda, Maryland, USA
Daniel C. Mathews
Affiliation:
National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, Bethesda, Maryland, USA
Erica M. Richards
Affiliation:
National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, Bethesda, Maryland, USA
Carlos A. Zarate Jr.
Affiliation:
National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, Bethesda, Maryland, USA Psychiatry and Behavioral Sciences, The George Washington University, Washington, DC, USA
*
*Address for correspondence: Dr. Mark J. Niciu, National Institutes of Health/National Institute of Mental Health, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, 10 Center Dr., Building 10/CRC, Room 7-5545, Bethesda, MD 20814-9692, USA. (Email [email protected])
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Abstract

In this second of two articles on second messenger/signal transduction cascades in major mood disorders, we will review the evidence in support of intracellular dysfunction and its rectification in the etiopathogenesis and treatment of bipolar disorder (BD). The importance of these cascades is highlighted by lithium's (the gold standard in BD psychopharmacology) ability to inhibit multiple critical loci in second messenger/signal transduction cascades including protein kinase C (involved in the IP3/PIP2 pathway) and GSK-3β (canonically identified in the Wnt/Fz/Dvl/GSK-3β cascade). As a result, and like major depressive disorder (MDD), more recent pathophysiological studies and rational therapeutic targets have been directed at these and other intracellular mediators. Even in the past decade, intracellular dysfunction in numerous neuroprotective/apoptotic cascades appears important in the pathophysiology and may be a future target for pharmacological interventions of BD.

Keywords

Bipolar disordersignal transductionsecond messengerintracellular cascadesmood stabilizerslithium
Type
Review Articles
Information
CNS Spectrums , Volume 18 , Issue 5 , October 2013 , pp. 242 - 251
Copyright
Copyright © Cambridge University Press 2013 

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Footnotes

The authors gratefully acknowledge the support of the Intramural Research Program of the NIMH/NIH (IRP-NIMH/NIH; Bethesda, MD, USA), and thank the 7SE Inpatient Mood and Anxiety Disorders Research Unit of the NIMH/NIH for their support. Funding for this work was supported by the IRP-NIMH-NIH by a NARSAD Independent Investigator to C.A.Z., and by the Brain & Behavior Mood Disorders Research Award to C.A.Z.

References

1.Allison, JH, Stewart, MA. Reduced brain inositol in lithium-treated rats. Nat New Biol. 1971; 233(43): 267–268.CrossRefGoogle ScholarPubMed
2.Machado-Vieira, R, Manji, HK, Zarate, CA Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009; 11(suppl 2): 92–109.CrossRefGoogle ScholarPubMed
3.Chen, G, Manji, HK, Wright, CB, Hawver, DB, Potter, WZ. Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells. Neuropsychopharmacology. 1996; 15(3): 271–280.Google ScholarPubMed
4.Bosetti, F, Bell, JM, Manickam, P. Microarray analysis of rat brain gene expression after chronic administration of sodium valproate. Brain Res Bull. 2005; 65(4): 331–338.CrossRefGoogle ScholarPubMed
5.Ertley, RN, Bazinet, RP, Lee, HJ, Rapoport, SI, Rao, JS. Chronic treatment with mood stabilizers increases membrane GRK3 in rat frontal cortex. Biol Psychiatry. 2007; 61(2): 246–249.CrossRefGoogle ScholarPubMed
6.Post, RM, Ballenger, JC, Uhde, TW, etal. Effect of carbamazepine on cyclic nucleotides in CSF of patients with affective illness. Biol Psychiatry. 1982; 17(9): 1037–1045.Google ScholarPubMed
7.Young, LT, Li, PP, Kish, SJ, Siu, KP, Warsh, JJ. Postmortem cerebral cortex Gs alpha-subunit levels are elevated in bipolar affective disorder. Brain Res. 1991; 553(2): 323–326.CrossRefGoogle ScholarPubMed
8.Friedman, E, Wang, HY. Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects. J Neurochem. 1996; 67(3): 1145–1152.CrossRefGoogle ScholarPubMed
9.Young, LT, Li, PP, Kamble, A, Siu, KP, Warsh, JJ. Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder. Am J Psychiatry. 1994; 151(4): 594–596.Google ScholarPubMed
10.Schreiber, G, Avissar, S, Danon, A, Belmaker, RH. Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry. 1991; 29(3): 273–280.CrossRefGoogle ScholarPubMed
11.Spleiss, O, van Calker, D, Scharer, L, etal. Abnormal G protein alpha(s)- and alpha(i2)-subunit mRNA expression in bipolar affective disorder. Mol Psychiatry. 1998; 3(6): 512–520.CrossRefGoogle ScholarPubMed
12.Fields, A, Li, PP, Kish, SJ, Warsh, JJ. Increased cyclic AMP-dependent protein kinase activity in postmortem brain from patients with bipolar affective disorder. J Neurochem. 1999; 73: 1704–1710.CrossRefGoogle ScholarPubMed
13.Chang, A, Li, PP, Warsh, JJ. Altered cAMP-dependent protein kinase subunit immunolabeling in post-mortem brain from patients with bipolar affective disorder. J Neurochem. 2003; 84(4): 781–791.CrossRefGoogle ScholarPubMed
14.Tardito, D, Mori, S, Racagni, G, etal. Protein kinase A activity in platelets from patients with bipolar disorder. J Affect Disord. 2003; 76(1–3): 249–253.CrossRefGoogle ScholarPubMed
15.Karege, F, Schwald, M, Papadimitriou, P, Lachausse, C, Cisse, M. The cAMP-dependent protein kinase A and brain-derived neurotrophic factor expression in lymphoblast cells of bipolar affective disorder. J Affect Disord. 2004; 79(1–3): 187–192.CrossRefGoogle ScholarPubMed
16.Ryan, MM, Lockstone, HE, Huffaker, SJ, etal. Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes. Mol Psychiatry. 2006; 11(10): 965–978.CrossRefGoogle ScholarPubMed
17.McDonald, ML, Macmullen, C, Liu, DJ, Leal, SM, Davis, RL. Genetic association of cyclic AMP signaling genes with bipolar disorder. Transl Psychiatry. 2012; 2: e169.CrossRefGoogle ScholarPubMed
18.Manji, HK, Lenox, RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry. 2000; 48(6): 518–530.CrossRefGoogle ScholarPubMed
19.Sadana, R, Dessauer, CW. Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies. Neurosignals. 2009; 17(1): 5–22.CrossRefGoogle Scholar
20.Ozaki, N, Chuang, DM. Lithium increases transcription factor binding to AP-1 and cyclic AMP-responsive element in cultured neurons and rat brain. J Neurochem. 1997; 69(6): 2336–2344.CrossRefGoogle ScholarPubMed
21.Tardito, D, Tiraboschi, E, Kasahara, J, Racagni, G, Popoli, M. Reduced CREB phosphorylation after chronic lithium treatment is associated with down-regulation of CaM kinase IV in rat hippocampus. Int J Neuropsychopharmacol. 2007; 10(4): 491–496.CrossRefGoogle ScholarPubMed
22.Ferrendelli, JA, Kinscherf, DA. Inhibitory effects of anticonvulsant drugs on cyclic nucleotide accumulation in brain. Ann Neurol. 1979; 5(6): 533–538.CrossRefGoogle ScholarPubMed
23.Van Calker, D, Steber, R, Klotz, KN, Greil, W. Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses. Eur J Pharmacol. 1991; 206(4): 285–290.CrossRefGoogle ScholarPubMed
24.Basselin, M, Chang, L, Chen, M, Bell, JM, Rapoport, SI. Chronic carbamazepine administration attenuates dopamine D2-like receptor-initiated signaling via arachidonic acid in rat brain. Neurochem Res. 2008; 33(7): 1373–1383.CrossRefGoogle ScholarPubMed
25.Di Daniel, E, Mudge, AW, Maycox, PR. Comparative analysis of the effects of four mood stabilizers in SH-SY5Y cells and in primary neurons. Bipolar Disord. 2005; 7(1): 33–41.CrossRefGoogle ScholarPubMed
26.Xie, N, Wang, C, Lin, Y, etal. The role of p38 MAPK in valproic acid induced microglia apoptosis. Neurosci Lett. 2010; 482(1): 51–56.CrossRefGoogle ScholarPubMed
27.Tsui, MM, Tai, WC, Wong, WY, Hsiao, WL. Selective G2/M arrest in a p53(Val135)-transformed cell line induced by lithium is mediated through an intricate network of MAPK and beta-catenin signaling pathways. Life Sci. 2012; 91(9–10): 312–321.CrossRefGoogle Scholar
28.Einat, H, Yuan, P, Gould, TD, etal. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci. 2003; 23(19): 7311–7316.CrossRefGoogle ScholarPubMed
29.Shimon, H, Agam, G, Belmaker, RH, Hyde, TM, Kleinman, JE. Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder. Am J Psychiatry. 1997; 154(8): 1148–1150.Google ScholarPubMed
30.Jope, RS, Song, L, Li, PP, etal. The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain. J Neurochem. 1996; 66(6): 2402–2409.CrossRefGoogle ScholarPubMed
31.Brown, AS, Mallinger, AG, Renbaum, LC. Elevated platelet membrane phosphatidylinositol-4,5-bisphosphate in bipolar mania. Am J Psychiatry. 1993; 150(8): 1252–1254.Google ScholarPubMed
32.Baum, AE, Akula, N, Cabanero, M, etal. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry. 2008; 13(2): 197–207.CrossRefGoogle ScholarPubMed
33.Xu, C, Li, PP, Cooke, RG, etal. TRPM2 variants and bipolar disorder risk: confirmation in a family-based association study. Bipolar Disord. 2009; 11(1): 1–10.CrossRefGoogle Scholar
34.Xu, C, Warsh, JJ, Wang, KS, Mao, CX, Kennedy, JL. Association of the iPLA2beta gene with bipolar disorder and assessment of its interaction with TRPM2 gene polymorphisms. Psychiatr Genet. In press.Google Scholar
35.Wang, HY, Friedman, E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry. 1996; 40(7): 568–575.CrossRefGoogle ScholarPubMed
36.Wang, H, Friedman, E. Increased association of brain protein kinase C with the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder. Biol Psychiatry. 2001; 50(5): 364–370.CrossRefGoogle ScholarPubMed
37.Friedman, E, Hoau Yan, W, Levinson, D, Connell, TA, Singh, H. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry. 1993; 33(7): 520–525.CrossRefGoogle ScholarPubMed
38.Wang, HY, Markowitz, P, Levinson, D, Undie, AS, Friedman, E. Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J Psychiatr Res. 1999; 33(2): 171–179.CrossRefGoogle ScholarPubMed
39.Pandey, GN, Dwivedi, Y, SridharaRao, J, etal. 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. Neuropsychopharmacology. 2002; 26(2): 216–228.CrossRefGoogle ScholarPubMed
40.Yoon, IS, Li, PP, Siu, KP, etal. Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder. Mol Psychiatry. 2001; 6(6): 678–683.CrossRefGoogle ScholarPubMed
41.Manji, HK, Etcheberrigaray, R, Chen, G, Olds, JL. Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme. J Neurochem. 1993; 61(6): 2303–2310.CrossRefGoogle ScholarPubMed
42.Chen, G, Masana, MI, Manji, HK. Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo. Bipolar Disord. 2000; 2(3 pt. 2): 217–236.CrossRefGoogle ScholarPubMed
43.Lenox, RH, Watson, DG, Patel, J, Ellis, J. Chronic lithium administration alters a prominent PKC substrate in rat hippocampus. Brain Res. 1992; 570(1–2): 333–340.CrossRefGoogle ScholarPubMed
44.Szabo, ST, Machado-Vieira, R, Yuan, P, etal. Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology. 2009; 56(1): 47–55.CrossRefGoogle ScholarPubMed
45.Chen, G, Manji, HK, Hawver, DB, Wright, CB, Potter, WZ. Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem. 1994; 63(6): 2361–2364.CrossRefGoogle ScholarPubMed
46.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(1): 307–316.Google Scholar
47.Hasegawa, H, Osada, K, Misonoo, A, etal. Chronic carbamazepine treatment increases myristoylated alanine-rich C kinase substrate phosphorylation in the rat cerebral cortex via down-regulation of calcineurin A alpha. Brain Res. 2003; 994(1): 19–26.CrossRefGoogle ScholarPubMed
48.Einat, H, Yuan, P, Szabo, ST, Dogra, S, Manji, HK. Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology. 2007; 55(3–4): 123–131.CrossRefGoogle ScholarPubMed
49.Bebchuk, JM, Arfken, CL, Dolan-Manji, S, etal. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch Gen Psychiatry. 2000; 57(1): 95–97.CrossRefGoogle ScholarPubMed
50.Kulkarni, J, Garland, KA, Scaffidi, A, etal. A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder. Psychoneuroendocrinology. 2006; 31(4): 543–547.CrossRefGoogle ScholarPubMed
51.Zarate, CA Jr., Singh, JB, Carlson, PJ, etal. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord. 2007; 9(6): 561–570.CrossRefGoogle ScholarPubMed
52.Yildiz, A, Guleryuz, S, Ankerst, DP, Ongur, D, Renshaw, PF. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry. 2008; 65(3): 255–263.CrossRefGoogle Scholar
53.Sylvia, LG, Peters, AT, Deckersbach, T, Nierenberg, AA. Nutrient-based therapies for bipolar disorder: a systematic review. Psychother Psychosom. 2013; 82(1): 10–19.CrossRefGoogle ScholarPubMed
54.van Calker, D, Belmaker, RH. The high affinity inositol transport system—implications for the pathophysiology and treatment of bipolar disorder. Bipolar Disord. 2000; 2(2): 102–107.CrossRefGoogle ScholarPubMed
55.Willmroth, F, Drieling, T, Lamla, U, etal. Sodium-myo-inositol co-transporter (SMIT-1) mRNA is increased in neutrophils of patients with bipolar 1 disorder and down-regulated under treatment with mood stabilizers. Int J Neuropsychopharmacol. 2007; 10(1): 63–71.CrossRefGoogle ScholarPubMed
56.Shaldubina, A, Johanson, RA, O'Brien, WT, etal. SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior. Mol Genet Metab. 2006; 88(4): 384–388.CrossRefGoogle ScholarPubMed
57.Klein, PS, Melton, DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A. 1996; 93(16): 8455–8459.CrossRefGoogle ScholarPubMed
58.Chen, G, Huang, LD, Jiang, YM, Manji, HK. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem. 1999; 72(3): 1327–1330.CrossRefGoogle ScholarPubMed
59.Roh, MS, Kang, UG, Shin, SY, etal. Biphasic changes in the Ser-9 phosphorylation of glycogen synthase kinase-3beta after electroconvulsive shock in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(1): 1–5.CrossRefGoogle ScholarPubMed
60.Polter, A, Beurel, E, Yang, S, etal. Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances. Neuropsychopharmacology. 2010; 35(8): 1761–1774.CrossRefGoogle ScholarPubMed
61.Gould, TD, Einat, H, O'Donnell, KC, etal. Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Neuropsychopharmacology. 2007; 32(10): 2173–2183.CrossRefGoogle ScholarPubMed
62.Benes, FM, Matzilevich, D, Burke, RE, Walsh, J. The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Mol Psychiatry. 2006; 11(3): 241–251.CrossRefGoogle Scholar
63.Kim, HW, Rapoport, SI, Rao, JS. Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Neurobiol Dis. 2010; 37(3): 596–603.CrossRefGoogle ScholarPubMed
64.Bei, E, Salpeas, V, Pappa, D, etal. Phosphorylation status of glucocorticoid receptor, heat shock protein 70, cytochrome c and Bax in lymphocytes of euthymic, depressed and manic bipolar patients. Psychoneuroendocrinology. 2009; 34(8): 1162–1175.CrossRefGoogle ScholarPubMed
65.Machado-Vieira, R, Pivovarova, NB, Stanika, RI, etal. The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol Psychiatry. 2011; 69(4): 344–352.CrossRefGoogle ScholarPubMed
66.Soeiro-de-Souza, MG, Salvadore, G, Moreno, RA, etal. Bcl-2 rs956572 polymorphism is associated with increased anterior cingulate cortical glutamate in euthymic bipolar I disorder. Neuropsychopharmacology. 2013; 38(3): 468–475.CrossRefGoogle ScholarPubMed
67.Kakiuchi, C, Iwamoto, K, Ishiwata, M, etal. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet. 2003; 35(2): 171–175.CrossRefGoogle ScholarPubMed
68.So, J, Warsh, JJ, Li, PP. Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder. Biol Psychiatry. 2007; 62(2): 141–147.CrossRefGoogle ScholarPubMed
69.Hayashi, A, Kasahara, T, Kametani, M, etal. Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder. Int J Neuropsychopharmacol. 2009; 12(1): 33–43.CrossRefGoogle ScholarPubMed
70.Kim, B, Kim, CY, Lee, MJ, Joo, YH. Preliminary evidence on the association between XBP1-116C/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders. Psychiatry Res. 2009; 168(3): 209–212.CrossRefGoogle ScholarPubMed
71.Song, L, Zhou, T, Jope, RS. Lithium facilitates apoptotic signaling induced by activation of the Fas death domain-containing receptor. BMC Neurosci. 2004; 5: 20.CrossRefGoogle ScholarPubMed
72.Gomez-Sintes, R, Lucas, JJ. NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy. J Clin Invest. 2010; 120(7): 2432–2445.CrossRefGoogle Scholar
73.Li, R, El-Mallahk, RS. A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency. Neurosci Lett. 2000; 294(3): 147–150.CrossRefGoogle ScholarPubMed
74.Lowthert, L, Leffert, J, Lin, A, etal. Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation. Biol Mood Anxiety Disord. 2012; 2(1): 15.CrossRefGoogle ScholarPubMed
75.Zarate, CA Jr., Payne, JL, Singh, J, etal. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004; 56(1): 54–60.CrossRefGoogle ScholarPubMed
76.Danial, NN, Gimenez-Cassina, A, Tondera, D. Homeostatic functions of BCL-2 proteins beyond apoptosis. Adv Exp Med Biol. 2010; 687: 1–32.CrossRefGoogle ScholarPubMed