title: Elucidating biological risk factors in suicide: role of protein kinase A.
abstract: Suicide is a major public health concern. Although there have been several studies of suicidal behavior that focused on the roles of psychosocial and sociocultural factors, these factors are of too little predictive value to be clinically useful. Therefore, research on the biological perspective of suicide has gained a stronghold and appears to provide a promising approach to identify biological risk factors associated with suicidal behavior. Recent studies demonstrate that an alteration in synaptic and structural plasticity is key to affective illnesses and suicide. Signal transduction molecules play an important role in such plastic events. Protein kinase A (PKA) is a crucial enzyme in the adenylyl cyclase signal transduction pathway and is involved in regulating gene transcription, cell survival, and plasticity. In this review, we critically and comprehensively discuss the role of PKA in suicidal behavior. Because stress is an important component of suicide, we also discuss whether stress affects PKA and how this may be associated with suicidal behavior. In addition, we also discuss the functional significance of the findings regarding PKA by describing the role of important PKA substrates (i.e., Rap1, cyclic adenosine monophosphate response element binding protein, and target gene brain-derived neurotrophic factor). These studies suggest the interesting possibility that PKA and related signaling molecules may serve as important neurobiological factors in suicide and may be relevant in target-specific therapeutic interventions for these disorders.
authors.affiliation: The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA. ydwivedi@psych.uic.edu
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Dwivedi
authors.forename: Ghanshyam N
authors.initials: GN
authors.lastname: Pandey
mesh_terms: D000262:Adenylyl Cyclases / Q000502:physiology; D014150:Antipsychotic Agents / Q000627:therapeutic use; D015415:Biomarkers; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000502:physiology; D005938:Glucocorticoids / Q000502:physiology; D006380:Helplessness, Learned; D006801:Humans; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology; D013315:Stress, Psychological / Q000201:enzymology / Q000523:psychology; D013405:Suicide / Q000523:psychology / Q000706:statistics & numerical data*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins; D000262:Adenylyl Cyclases
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9849-54
references.pmid: 9707564
references.citation: Curr Opin Neurobiol. 2004 Jun;14(3):311-7
references.pmid: 15194111
references.citation: Cell. 1997 Apr 4;89(1):73-82
references.pmid: 9094716
references.citation: J Immunol. 1991 Sep 1;147(5):1628-35
references.pmid: 1908879
references.citation: Cell. 2000 Oct 13;103(2):193-200
references.pmid: 11057893
references.citation: Eur J Neurosci. 2005 Mar;21(5):1299-303
references.pmid: 15813939
references.citation: Crit Rev Oncog. 1992;3(4):321-38
references.pmid: 1329990
references.citation: Neuron. 2002 Mar 28;34(1):13-25
references.pmid: 11931738
references.citation: Biochemistry. 1995 Feb 28;34(8):2447-54
references.pmid: 7873523
references.citation: Neurosci Lett. 2002 Aug 16;328(3):261-4
references.pmid: 12147321
references.citation: Mol Psychiatry. 2007 Dec;12(12):1079-88
references.pmid: 17700574
references.citation: J Biol Chem. 2002 May 24;277(21):18810-6
references.pmid: 11886856
references.citation: Trends Neurosci. 2000 Feb;23(2):48-53
references.pmid: 10652539
references.citation: J Biochem. 2003 Oct;134(4):479-84
references.pmid: 14607972
references.citation: Science. 2002 May 31;296(5573):1636-9
references.pmid: 12040175
references.citation: Am J Psychiatry. 2000 Jan;157(1):115-8
references.pmid: 10618023
references.citation: Mol Cell Biol. 1993 Apr;13(4):2332-41
references.pmid: 8455615
references.citation: J Pharmacol Exp Ther. 2002 Apr;301(1):197-209
references.pmid: 11907174
references.citation: Am J Psychiatry. 2002 Jan;159(1):66-73
references.pmid: 11772692
references.citation: Arch Gen Psychiatry. 1996 Dec;53(12):1145-52
references.pmid: 8956681
references.citation: Neuroscience. 2009 Feb 18;158(4):1406-15
references.pmid: 19111907
references.citation: Brain Res. 1996 Jun 3;723(1-2):37-45
references.pmid: 8813380
references.citation: J Biol Chem. 2000 Nov 3;275(44):34433-41
references.pmid: 10950954
references.citation: Int J Neuropsychopharmacol. 2009 Oct;12(9):1223-32
references.pmid: 19573263
references.citation: J Clin Psychiatry. 2000;61 Suppl 3:4-9
references.pmid: 10724127
references.citation: Biol Psychiatry. 2000 Oct 15;48(8):721-31
references.pmid: 11063969
references.citation: Schizophr Res. 2003 Mar 1;60(1):47-55
references.pmid: 12505137
references.citation: Epidemiology. 1997 Nov;8(6):671-7
references.pmid: 9345668
references.citation: Mol Psychiatry. 2002;7(2):208-12
references.pmid: 11840314
references.citation: J Biol Chem. 1988 Dec 15;263(35):18965-71
references.pmid: 3143720
references.citation: Biol Psychiatry. 1989 Feb 1;25(3):355-9
references.pmid: 2536563
references.citation: J Biol Chem. 1998 Jan 9;273(2):669-72
references.pmid: 9422713
references.citation: Endocrinology. 1992 Sep;131(3):1377-82
references.pmid: 1324160
references.citation: Prog Brain Res. 2008;169:97-115
references.pmid: 18394470
references.citation: Biophys Chem. 2007 Jan;125(1):59-71
references.pmid: 16863676
references.citation: Stress. 2004 Dec;7(4):221-31
references.pmid: 16019587
references.citation: J Biol Chem. 1968 Jul 10;243(13):3763-5
references.pmid: 4298072
references.citation: Semin Cancer Biol. 1994 Aug;5(4):285-94
references.pmid: 7803765
references.citation: J Neural Transm Gen Sect. 1993;94(1):63-9
references.pmid: 8129882
references.citation: J Clin Psychiatry. 2004 May;65(5):679-85
references.pmid: 15163255
references.citation: J Neurosci. 2000 May 15;20(10):RC75
references.pmid: 10783399
references.citation: Mol Psychiatry. 2001 Sep;6(5):540-6
references.pmid: 11526468
references.citation: J Am Acad Child Adolesc Psychiatry. 1993 Jan;32(1):95-105
references.pmid: 8428891
references.citation: J Affect Disord. 2000 Nov;60(3):181-9
references.pmid: 11074106
references.citation: Biol Psychiatry. 2004 Feb 1;55(3):234-43
references.pmid: 14744463
references.citation: Neuropsychopharmacology. 2005 Aug;30(8):1548-56
references.pmid: 15920506
references.citation: Biol Psychiatry. 2006 Jun 15;59(12):1116-27
references.pmid: 16631126
references.citation: J Neurochem. 1993 Sep;61(3):890-8
references.pmid: 8395565
references.citation: J Neurochem. 2001 May;77(3):916-28
references.pmid: 11331420
references.citation: J Psychopharmacol. 2001 Jun;15(2):127-35
references.pmid: 11448086
references.citation: Front Biosci. 2000 Aug 01;5:D678-93
references.pmid: 10922298
references.citation: Brain Res. 1997 May 30;758(1-2):223-8
references.pmid: 9203552
references.citation: Arch Gen Psychiatry. 2003 Aug;60(8):804-15
references.pmid: 12912764
references.citation: CNS Drugs. 2003;17(4):273-80; discussion 281-3
references.pmid: 12665398
references.citation: Brain Res. 1990 Jun 18;520(1-2):90-102
references.pmid: 2207649
references.citation: Mol Psychiatry. 1998 Nov;3(6):512-20
references.pmid: 9857977
references.citation: Lancet. 1998 Nov 28;352(9142):1754-5
references.pmid: 9848357
references.citation: Proc Natl Acad Sci U S A. 1987 Aug;84(15):5192-6
references.pmid: 3037538
references.citation: Annu Rev Biochem. 1987;56:615-49
references.pmid: 3113327
references.citation: J Biol Chem. 1990 Nov 15;265(32):19502-6
references.pmid: 2174040
references.citation: Mol Psychiatry. 2001 Jan;6(1):44-9
references.pmid: 11244484
references.citation: Trends Pharmacol Sci. 1999 Jun;20(6):237-45
references.pmid: 10366866
references.citation: Arch Gen Psychiatry. 2003 Mar;60(3):273-82
references.pmid: 12622660
references.citation: J Neurosci. 1997 Jan 1;17(1):83-90
references.pmid: 8987738
references.citation: Crit Rev Clin Lab Sci. 1999 Aug;36(4):275-328
references.pmid: 10486703
references.citation: Biochem Pharmacol. 1997 Aug 1;54(3):325-39
references.pmid: 9278091
references.citation: J Biol Chem. 1990 Dec 15;265(35):21561-6
references.pmid: 2147685
references.citation: J Biol Chem. 1999 Apr 9;274(15):10086-93
references.pmid: 10187789
references.citation: Pharmacol Biochem Behav. 1982 Mar;16(3):449-54
references.pmid: 7200610
references.citation: Neuroendocrinology. 1992 Oct;56(4):491-501
references.pmid: 1335553
references.citation: Am J Psychiatry. 1995 Feb;152(2):183-90
references.pmid: 7840350
references.citation: J Psychiatry Neurosci. 1999 Mar;24(2):116-21
references.pmid: 10212553
references.citation: Commun Psychopharmacol. 1979;3(5):371-3
references.pmid: 575771
references.citation: Cell Signal. 1999 Jul;11(7):465-77
references.pmid: 10405757
references.citation: Neurosci Behav Physiol. 1992 Jan-Feb;22(1):59-65
references.pmid: 1614620
references.citation: Cereb Cortex. 2002 Apr;12(4):386-94
references.pmid: 11884354
references.citation: Endocr Rev. 1993 Oct;14(5):632-50
references.pmid: 8262010
references.citation: Natl Vital Stat Rep. 2001 Oct 9;49(12):1-40
references.pmid: 11694979
references.citation: Neuropsychobiology. 2007;56(2-3):93-7
references.pmid: 18037819
references.citation: Brain Res Mol Brain Res. 2005 May 20;136(1-2):29-37
references.pmid: 15893584
references.citation: Rev Neurosci. 2002;13(3):195-208
references.pmid: 12405224
references.citation: Arch Gen Psychiatry. 1990 Nov;47(11):1029-34
references.pmid: 2241505
references.citation: Nucleic Acids Res. 1988 Aug 11;16(15):7719
references.pmid: 3137530
references.citation: J Neurosci. 1996 Apr 1;16(7):2365-72
references.pmid: 8601816
references.citation: Arch Suicide Res. 2007;11(3):235-46
references.pmid: 17558608
references.citation: J Psychiatry Neurosci. 2001;26 Suppl:S17-22
references.pmid: 11590965
references.citation: Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1571-6
references.pmid: 8643673
references.citation: Annu Rev Pharmacol Toxicol. 1997;37:167-203
references.pmid: 9131251
references.citation: Sci STKE. 2004 Sep 14;2004(251):PE45
references.pmid: 15383672
references.citation: Schizophr Res. 2005 Mar 1;73(2-3):139-45
references.pmid: 15653256
references.citation: Ann N Y Acad Sci. 1997 Dec 29;836:220-32
references.pmid: 9616801
references.citation: Exp Cell Res. 1999 Nov 25;253(1):157-65
references.pmid: 10579920
references.citation: Arch Gen Psychiatry. 2003 Jan;60(1):82-91
references.pmid: 12511175
references.citation: Eur Neuropsychopharmacol. 1998 May;8(2):89-94
references.pmid: 9619686
references.citation: J Psychiatr Res. 2000 Mar-Apr;34(2):99-104
references.pmid: 10758250
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2009 Aug 1;33(5):849-53
references.pmid: 19371767
references.citation: J Biol Chem. 1991 Apr 5;266(10):6571-7
references.pmid: 1901063
references.citation: Biol Psychiatry. 2005 Aug 15;58(4):315-24
references.pmid: 15939410
references.citation: J Biol Chem. 1986 Nov 25;261(33):15360-3
references.pmid: 3023318
references.citation: Cell Calcium. 1999 Mar;25(3):219-26
references.pmid: 10378083
references.citation: Psychiatr Clin North Am. 1985 Jun;8(2):203-14
references.pmid: 3895188
references.citation: Biol Psychiatry. 2000 Oct 15;48(8):791-800
references.pmid: 11063975
references.citation: Am J Psychiatry. 1997 Feb;154(2):199-204
references.pmid: 9016268
references.citation: Ann N Y Acad Sci. 1986;487:294-300
references.pmid: 2882719
references.citation: Am J Med Genet. 2002 Dec 8;114(8):980-7
references.pmid: 12457397
references.citation: J Exp Psychol. 1967 May;74(1):1-9
references.pmid: 6032570
references.citation: Science. 1995 Oct 27;270(5236):593-8
references.pmid: 7570017
references.citation: J Biol Chem. 1999 Sep 3;274(36):25842-8
references.pmid: 10464325
references.citation: J Pharmacol Exp Ther. 2000 Jul;294(1):103-16
references.pmid: 10871301
references.citation: Arch Gen Psychiatry. 2000 Apr;57(4):349-56
references.pmid: 10768696
references.citation: Int J Neuropsychopharmacol. 2007 Oct;10(5):621-9
references.pmid: 16978443
references.citation: Am J Psychiatry. 1975 Jun;132(6):650-1
references.pmid: 1124812
references.citation: Epidemiol Rev. 1987;9:51-69
references.pmid: 2445596
references.citation: Mol Cell Biol. 1998 Mar;18(3):1416-23
references.pmid: 9488457
references.citation: Issues Ment Health Nurs. 2003 Jan-Feb;24(1):27-43
references.pmid: 12735073
references.citation: Arch Gen Psychiatry. 1999 Mar;56(3):248-53
references.pmid: 10078502
references.citation: Neuroreport. 1997 Dec 1;8(17):3791-4
references.pmid: 9427372
references.citation: J Biol Chem. 2000 Oct 13;275(41):31921-9
references.pmid: 10931830
references.citation: Nat Rev Mol Cell Biol. 2001 May;2(5):369-77
references.pmid: 11331911
references.citation: Science. 1991 May 10;252(5007):802-8
references.pmid: 1902986
references.citation: Nature. 1997 Oct 23;389(6653):856-60
references.pmid: 9349818
references.citation: Ann N Y Acad Sci. 1997 Dec 29;836:253-68
references.pmid: 9616803
references.citation: Schizophr Res. 2002 Oct 1;57(2-3):147-56
references.pmid: 12223245
references.citation: Am J Psychiatry. 1997 Feb;154(2):211-7
references.pmid: 9016270
references.citation: J Neurosci. 2000 Mar 15;20(6):2238-46
references.pmid: 10704499
references.citation: J Biol Chem. 1984 Aug 10;259(15):9840-6
references.pmid: 6086653
references.citation: Biol Psychiatry. 2000 Oct 15;48(8):732-9
references.pmid: 11063970
references.citation: Cell. 1995 Jan 27;80(2):249-57
references.pmid: 7834744
references.citation: J Biol Chem. 1996 Jun 28;271(26):15736-42
references.pmid: 8662989
references.citation: Proc Natl Acad Sci U S A. 1988 Jun;85(11):3703-7
references.pmid: 3375237
references.citation: Brain Res. 1994 Jan 7;633(1-2):297-304
references.pmid: 8137164
references.citation: Semin Clin Neuropsychiatry. 2002 Oct;7(4):281-92
references.pmid: 12382210
references.citation: Neuron. 1998 Oct;21(4):869-83
references.pmid: 9808472
references.citation: Nature. 1996 Jul 4;382(6586):83-7
references.pmid: 8657310
references.citation: Brain Res. 2001 Apr 20;898(2):224-31
references.pmid: 11306008
references.citation: Annu Rev Neurosci. 2001;24:677-736
references.pmid: 11520916
references.citation: Arch Gen Psychiatry. 2001 Jul;58(7):649-50
references.pmid: 11448370
references.citation: Biol Psychiatry. 2009 Feb 15;65(4):319-28
references.pmid: 18930453
references.citation: Am J Psychiatry. 2001 Sep;158(9):1449-54
references.pmid: 11532730
references.citation: Annu Rev Neurosci. 1999;22:105-22
references.pmid: 10202533
references.citation: Mol Psychiatry. 2007 Nov;12(11):981-3
references.pmid: 17957235
references.citation: Exp Neurol. 2003 Mar;180(1):32-45
references.pmid: 12668147
references.citation: Am J Psychiatry. 1999 Jul;156(7):990-9
references.pmid: 10401441
references.citation: Am J Psychiatry. 1999 Oct;156(10):1590-5
references.pmid: 10518171
references.citation: Neuron. 2003 Jul 17;39(2):309-25
references.pmid: 12873387
references.citation: Biol Psychiatry. 2004 Mar 15;55(6):570-7
references.pmid: 15013825
references.citation: Mol Endocrinol. 1999 May;13(5):659-69
references.pmid: 10319317
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jan 30;31(1):78-85
references.pmid: 16904252
references.citation: Ann Med. 2010 Mar;42(2):87-96
references.pmid: 20166812
references.citation: J Neurosci. 1998 May 15;18(10):3639-49
references.pmid: 9570795
references.citation: Mol Psychiatry. 2006 Jan;11(1):86-98
references.pmid: 16172610
references.citation: J Neural Transm (Vienna). 2003 Jun;110(6):671-80
references.pmid: 12768362
references.citation: J Affect Disord. 2007 Aug;101(1-3):239-44
references.pmid: 17173978