Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania.
Considerable biochemical evidence suggests that the protein kinase C (PKC) signaling cascade may be a convergent point for the actions of anti-manic agents, and that excessive PKC activation can disrupt prefrontal cortical regulation of thinking and behavior. To date, however, brain protein targets of PKC's anti-manic effects have not been fully identified. Here we showed that PKC activity was enhanced in the prefrontal cortex of animals treated with the psychostimulant amphetamine. Phosphorylation of MARCKS, a marker of PKC activity, was increased in the prefrontal cortex of animals treated with the psychostimulant amphetamine, as well as in sleep-deprived animals (another animal model of mania), but decreased in lithium-treated animals. The antidepressant imipramine, which shows pro-manic properties in patients with bipolar disorder (BPD), also enhanced phospho-MARCKS in prefrontal cortex in vivo. We further explored the functional targets of PKC in mania-associated behaviors. Neurogranin is a brain-specific, postsynaptically located PKC substrate. PKC phosphorylation of neurogranin was robustly increased by pro-manic manipulations and decreased by anti-manic agents. PKC phosphorylation of the NMDA receptor site GluN1S896 and the AMPA receptor site GluA1T840 was also enhanced in the prefrontal cortex of animals treated with the antidepressant imipramine, as well as in behaviorally sleep-deprived animals, in striking contrast to the reduced activity seen in lithium-treated animals. These results suggest that PKC may play an important role in regulating NMDA and AMPA receptor functions. The biochemical profile of the PKC pathway thus encompasses both pro- and anti-manic effects on behavior. These results suggest that PKC modulators or their intracellular targets may ultimately represent novel avenues for the development of new therapeutics for mood disorders.
Szabo
Steven T
ST
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Building 35, 1C912, Bethesda, MD 20892, USA.
Machado-Vieira
Rodrigo
R
Yuan
Peixiong
P
Wang
Yun
Y
Wei
Yanling
Y
Falke
Cynthia
C
Cirelli
Chiara
C
Tononi
Giulio
G
Manji
Husseini K
HK
Du
Jing
J
D000661:Amphetamine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D051579:Neurogranin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D017470:Receptors, Glutamate / Q000378:metabolism*; D012892:Sleep Deprivation
D000929:Antidepressive Agents, Tricyclic; D000697:Central Nervous System Stimulants; D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D017470:Receptors, Glutamate; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D051579:Neurogranin; D000661:Amphetamine; D011493:Protein Kinase C; D018021:Lithium Chloride; D007099:Imipramine
Sheng Li Ke Xue Jin Zhan. 2003 Apr;34(2):111-5
12889141
Biol Psychiatry. 2000 Sep 15;48(6):518-30
11018224
Hum Mol Genet. 2002 Jun 1;11(12):1373-80
12023979
Brain Res. 1992 Jan 20;570(1-2):333-40
1617424
J Biochem. 1998 Apr;123(4):760-5
9538272
Nat Rev Drug Discov. 2008 May;7(5):426-37
18425072
Biol Psychiatry. 1997 Mar 15;41(6):649-56
9066988
Ann N Y Acad Sci. 2003 Nov;1003:273-91
14684452
J Psychiatry Neurosci. 2007 May;32(3):160-1
17476362
Prog Neuropsychopharmacol Biol Psychiatry. 1997 Apr;21(3):455-86
9153068
Prog Neuropsychopharmacol Biol Psychiatry. 1997 Apr;21(3):507-29
9153070
J Neurochem. 1994 Dec;63(6):2361-4
7964759
Biol Psychiatry. 2008 Feb 15;63(4):349-52
17643398
Biol Psychiatry. 2003 Apr 15;53(8):707-42
12706957
Nat Neurosci. 2008 Feb;11(2):200-8
18204445
Biol Psychiatry. 2006 Apr 15;59(8):713-20
16460696
J Neurosci. 2000 Jan 1;20(1):89-102
10627585
Synapse. 2003 Dec 1;50(3):212-22
14515339
Neuropsychologia. 2003;41(11):1474-83
12849765
Biol Psychiatry. 2006 Jun 15;59(12):1151-9
16566899
Annu Rev Pharmacol Toxicol. 1993;33:45-70
8098596
Neurosurgery. 1993 Sep;33(3):495-501; discussion 501
8413883
Neuropsychobiology. 2007;55(3-4):123-31
17641532
Bipolar Disord. 2000 Sep;2(3 Pt 2):217-36
11249800
Arch Gen Psychiatry. 2004 Jul;61(7):685-93
15237080
Neuropharmacology. 2001 Nov;41(6):672-9
11640921
Mol Psychiatry. 1998 Nov;3(6):534-8
9857980
Mol Psychiatry. 2008 Feb;13(2):197-207
17486107
J Clin Psychiatry. 1998 Jul;59(7):374-9
9714266
J Neurosci. 2004 Jul 21;24(29):6578-89
15269270
Harefuah. 2004 Jun;143(6):420-5, 462
15524099
Mol Cell Neurosci. 2007 Sep;36(1):86-94
17689977
CNS Spectr. 2005 Oct;10(10):808-19
16400244
Neuropharmacology. 1992 Dec;31(12):1211-22
1361666
Neuron Glia Biol. 2004 Aug;1(3):231-43
18634600
J Neurochem. 1999 Dec;73(6):2299-309
10582587
Curr Psychiatry Rep. 2007 Dec;9(6):467-74
18221626
Trends Neurosci. 2002 Dec;25(12):610-5
12446127
Biol Psychiatry. 2006 Jun 1;59(11):1006-20
16487491
Am J Psychiatry. 1999 Dec;156(12):1986-8
10588416
Bipolar Disord. 1999 Dec;1(2):81-6
11252663
Biol Psychiatry. 1996 Oct 1;40(7):568-75
8886289
Science. 2005 Nov 25;310(5752):1340-3
16311338
Neuropsychologia. 1987;25(2):359-65
3601041
Neuron. 2006 Jul 20;51(2):213-25
16846856
Science. 2004 Oct 29;306(5697):882-4
15514161
J Neurochem. 1993 Nov;61(5):1722-30
8228988
J Biol Chem. 1997 Dec 26;272(52):32727-30
9407043
Curr Psychiatry Rep. 2000 Dec;2(6):479-89
11122999
J Neurochem. 1996 Jun;66(6):2402-9
8632163
Neuropharmacology. 2007 Jul;53(1):27-36
17543354
Arch Gen Psychiatry. 2008 Mar;65(3):255-63
18316672
Neuron. 2007 Mar 1;53(5):703-17
17329210
Arch Gen Psychiatry. 2003 Jun;60(6):601-9
12796223
Neuropharmacology. 1992 Dec;31(12):1201-10
1361665
Neuropsychopharmacology. 2007 Apr;32(4):793-802
16936714
Neuropsychopharmacology. 2002 Jan;26(1):14-7
11751028
Neuron. 2003 Apr 24;38(2):157-60
12718851
Pharmacol Ther. 2001 Feb;89(2):149-70
11316518
Biol Psychiatry. 2006 Apr 1;59(7):611-8
16414030
J Pharmacol Exp Ther. 1998 Apr;285(1):307-16
9536026
Biol Psychiatry. 1999 Nov 15;46(10):1328-51
10578449
J Affect Disord. 2003 Jan;73(1-2):123-31
12507745
Eur Neuropsychopharmacol. 1995;5 Suppl:89-93
8775765
Neurochem Int. 2005 Jul;47(1-2):84-91
15936117
J Clin Psychiatry. 1996;57 Suppl 13:23-31; discussion 32-3
8970502
J Neurosci. 2000 Jun 15;20(12):4480-8
10844017
Ann N Y Acad Sci. 2003 Nov;1003:378-80
14684466
Arch Gen Psychiatry. 2000 Jan;57(1):95-7
10632242
J Psychiatr Res. 2003 Sep-Oct;37(5):421-32
12849934
J Biol Chem. 2000 Jun 9;275(23):17894-9
10749878
Int J Neuropsychopharmacol. 2007 Oct;10(5):621-9
16978443
Neuropsychopharmacology. 2007 Dec;32(12):2511-9
17356571
J Neurochem. 2004 Jun;89(5):1119-25
15147504
Curr Drug Targets. 2001 Sep;2(3):299-312
11554554
Biol Psychiatry. 1998 Nov 1;44(9):909-11
9807646
J Neurochem. 1993 Dec;61(6):2303-10
8245981
Bipolar Disord. 2007 Sep;9(6):561-70
17845270
Synapse. 1997 Jul;26(3):281-91
9183817
Biochemistry. 2000 Jun 20;39(24):7291-9
10852729
J Clin Psychiatry. 2000;61 Suppl 9:5-15
10826655
J Neurosci. 2008 Jan 2;28(1):68-79
18171924
Pharmacol Ther. 2006 Dec;112(3):810-32
16904750
J Neurosci. 1999 May 15;19(10):3674-80
10233999
Exp Neurol. 2008 May;211(1):7-10
18291371
J Neurochem. 2002 Nov;83(3):704-12
12390532
Neuron. 1996 Jun;16(6):1179-88
8663994
J Biol Chem. 2002 May 31;277(22):19498-505
11912190
J Clin Psychiatry. 1999 Nov;60(11):733-40
10584760
Biofactors. 1990 Jul;2(3):171-8
2116134
Neurology. 1986 Feb;36(2):212-6
3945393