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Original Article |

Decreased Catalytic Activity and Expression of Protein Kinase C Isozymesin Teenage Suicide Victims:  A Postmortem Brain Study FREE

Ghanshyam N. Pandey, PhD; Yogesh Dwivedi, PhD; Hooriyah S. Rizavi, MS; Xinguo Ren, MD; Robert R. Conley, MD
[+] Author Affiliations

From the Psychiatric Institute, Department of Psychiatry, Universityof Illinois at Chicago (Drs Pandey, Dwivedi, and Ren and Ms Rizavi); and theMaryland Psychiatric Research Center, Baltimore (Dr Conley).


Arch Gen Psychiatry. 2004;61(7):685-693. doi:10.1001/archpsyc.61.7.685.
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Background  Teenage suicide is a major public health concern. Although there is some understanding of the psychosocial factors associated with teenage suicide, little is known about the neurobiologic factors of teenage suicide. Protein kinase C (PKC) is a critical phosphorylating enzyme in the phosphoinositide signaling pathway (which is involved in many physiologic functions in the brain and has been implicated in the pathogenesis of mood disorders) and is also a target for the therapeutic action of mood-stabilizing drugs.

Objective  To examine whether the pathogenesis of teenage suicide is associated with changes in PKC.

Design  Postmortem brain study.

Participants  Seventeen teenage suicide victims and 17 nonpsychiatric control subjects.

Main Outcome Measures  Catalytic activity of PKC and protein and messenger RNA levels of various PKC isozymes, such as PKC α, β, and γ, were determined in the prefrontal cortex and hippocampus of both groups.

Results  Protein kinase C activity was statistically significantly decreased in membrane and cytosol fractions of the prefrontal cortex and hippocampus of teenage suicide victims compared with control subjects. Statistically significant decreases in protein levels of PKC α, βI, βII, and γ isozymes were also observed in both of these fractions. These decreases were associated with decreases in levels of their respective messenger RNAs.

Conclusion  Because many physiologic functions are mediated through phosphorylation by PKC and because PKC is a target for the therapeutic action of psychoactive drugs, our findings indicate that the pathogenesis of teenage suicide may be associated with abnormalities in PKC and that PKC may be a target for therapeutic intervention in patients with suicidal behavior.

Figures in this Article

Suicide is a major public health concern,1 andapproximately 30 000 people die of suicide each year in the United Statesalone.2 Teenage suicide is a special concernbecause it is the second leading cause of death among teenagers and becausethe suicide rate in the past 10 to 20 years has increased 4-fold in the whiteteenage male population.3 Whereas there issome understanding of the psychosocial and psychological factors associatedwith teenage suicide and of the neurobiologic abnormalities of adult suicide,little is known about the neurobiologic characteristics of teenage suicide.Studies49 ofthe neurobiologic factors in adult suicide have indicated abnormalities inneurotransmitter receptors, such as 5-hydroxytryptamine 2A (5-HT2A)and α- or β-adrenergic receptors, and in the receptor-linked signalingsystems, namely, adenylate cyclase and the phosphoinositide signaling system,to which these receptors are linked.

The characteristics of teenage suicide may be similar to those of adultsuicide in some respects but may differ in others. Besides psychiatric disorders,other risk factors for suicide include psychosocial stressors, impulsivity,and aggression.10 In teenagers, the major drivingfactor leading to suicide is aggressive/impulsive behavior,10,11 whichhas been implicated in abnormalities in serotonin function.12 Ina recent study, our group5 found that the numberof 5-HT2A receptors was increased in the prefrontal cortex (PFC)and hippocampus of suicide victims, which was associated with an increasein protein and messenger RNA (mRNA) expression. Although these studies indicatedabnormalities in 5-HT2A receptors, the biochemical consequencesand the physiologic significance of this observation remain unclear.

Protein kinase C (PKC) is an important component of the phosphoinositidesignaling system13,14 to which5-HT2A and several other receptors, such as 5-HT2C, α1-adrenergic, and muscarinic M1 receptors, are linked andmediate their functional response. In the phosphoinositide signaling system,stimulation of these receptors activates the effector phospholipase C, whichcauses hydrolysis of the substrate inositol-4,5-biphosphate and results inthe formation of 2 second messengers, diacylglycerol and inositol triphosphate.15 Diacylglycerol activates the phospholipid- and calcium-dependentPKC and increases the affinity of the enzyme for calcium.16 Inositoltriphosphate, on the other hand, mobilizes calcium from intracellular stores.14 Activation of PKC is associated with translocationof the enzyme from cytoplasm to membrane.17 OncePKC has been activated, it is involved in the phosphorylation of several membranal,cytosolic, and nuclear proteins.

Protein kinase C is a key regulatory enzyme present in various tissues,including the brain, and it is localized presynaptically and postsynaptically.13,18 The expression of PKC in the brainregion is isoform specific.19 Heterogeneityexists in PKC, and 12 different isozymes have now been described.16 Each individual isozyme is involved in specific cellularresponses, such as migration, proliferation, atrophy, apoptosis, and secretion,which suggests that these isozymes are important in clinical disorders.14,1921 ThePKC family has been subgrouped into 3 classes: conventional, which includes α, βI, βII,and γ; novel, which includes δ, ϵ, and φ; and atypical.14,16 Each isozyme is encoded by a uniquegene, except for βI and βII isozymes, which are the splicing productsof the same transcript.22 The biochemical propertiesof each isozyme have been identified with respect to activation or to phosphorylation,proteolytic activation, degradation, and substrate specificity.22

There is direct and indirect evidence20,23,24 suggestingthat PKC may play a crucial role in mental disorders. An earlier study25 examined the role of PKC in suicide by determining[3H]phorbol 12,13-dibutyrate (PDBu) binding in the PFC and hippocampusof teenage suicide victims. [3H]phorbol 12,13-dibutyrate is a highlyspecific ligand that measures regulatory subunits of PKC.26,27 Theauthors25 found that [3H]PDBu bindingwas significantly decreased in the PFC and hippocampus of teenage suicidevictims compared with nonpsychiatric control subjects. This study providedpreliminary evidence of abnormalities of PKC in teenage suicide; however,[3H]PDBu, as stated previously, measures only regulatory subunitsof PKC, and it was not clear from this study whether the decrease in PKC bindingsites was associated with either changes in catalytic activity or changesin the level of any specific isozyme. Because each isozyme is related to specificfunctions and is region specific, we determined the catalytic activity ofPKC and the protein levels of various isozymes in membrane and cytosol fractionsof the PFC and hippocampus obtained from postmortem brain samples of teenagesuicide victims and nonpsychiatric control subjects. To further examine whetherany changes in the isozymes are related to altered transcription, we determinedthe mRNA levels of these isozymes in total RNA.

PARTICIPANTS

The right hemispheres of the PFC (Brodmann area 9) and hippocampus from17 teenage suicide victims and 17 nonpsychiatric teenage control subjectsobtained from the Brain Collection Program of the Maryland Psychiatric ResearchCenter, in collaboration with the Medical Examiner's Office of the State ofMaryland, were used. Brain samples were free of neuropathologic abnormalitiesand human immunodeficiency virus antibodies. Toxicologic data were obtainedby analysis of urine and blood samples from the participants.

All patients in this study were diagnosed based on the Diagnostic Evaluation After Death28 andthe Structured Clinical Interviews for the DSM-III-R asdescribed earlier.29 Two senior psychiatristsprovided independent lifetime DSM-III-R diagnoses.Controls were verified as being free of mental illness and substance abuse.The protocols for tissue sampling and retrospective assessments were approvedby the institutional review board of the University of Maryland. This studywas also approved by the institutional review board of the University of Illinoisat Chicago. The demographic, clinical, and toxicologic characteristics ofthe participants are provided in Table 1.

Table Graphic Jump LocationDemographic, Clinical, and Toxicologic Characteristics of 17 TeenageSuicide Victims and 17 Control Subjects
DETERMINATION OF PKC ACTIVITY IN MEMBRANE AND CYTOSOL FRACTIONS

Protein kinase C activity in membrane and cytosol fractions of bothbrain areas was measured by using the procedure described in a previous study.30 Assay tubes contained 25 µL of a componentmixture (3mM Ca/[C3H3O2]2, L-α-phosphatidyl-L-serine [75 µg/mL], phorbol 12-myristate13-acetate [6 µg/mL], 225µM substrate peptide, and 7.5mM dithiothreitolin 50mM Tris hydrochloride containing 0.05% sodium azide, pH 75) and 25 µLof the membrane or cytosol fraction. The reaction was initiated by the additionof 25 µL of magnesium–adenosine triphosphate buffer ([γ-32P]adenosine triphosphate [10 µCi/mL {370 000 Bq/mL}], 1.2mMadenosine triphosphate, 72mM magnesium chloride, and 30mM HEPES [4-(2-hydroxyethyl)poperazine-1-ethanesulfonicacid], pH 7.4) and incubated for 15 minutes at 37°C. The reaction wasterminated by the addition of 100 µL of 300mM orthophosphoric acid.An aliquot of the solution from each tube (35 µL) was blotted onto individualpeptide-binding papers, and the retained radioactivity was counted.

QUANTITATION OF PKC ISOZYMES IN MEMBRANE AND CYTOSOL FRACTIONS BY WESTERNBLOT

Immunolabeling of PKC α, βI, βII, and γ was determinedas described in a previous study.30 Equal volumesof tissue samples (30 µg of protein in 20 µL) were loaded onto7.5% (weight per volume) polyacrylamide gel and electrophoresed. The blotswere initially developed using polyclonal anti–PKC α, βI, βII,or γ antibody (1:3000-1:5000 dilution) and subsequently using β-actinmonoclonal antibody (1:5000 dilution). The levels of PKC isozymes were calculatedas a ratio of the optical density of the PKC antibody of interest to the opticaldensity of β-actin antibody.

QUANTITATIVE RT-PCR ANALYSIS OF mRNA LEVELS OF PKC ISOZYMES AND NEURON-SPECIFICENOLASE

Messenger RNA levels of PKC isozymes and neuron-specific enolase (NSE)were determined in total RNA as described in detail in a previous study.31 Internal standards were used to determine the quantitationof PKC isozyme and NSE mRNAs.31 Primer pairswere designed to allow amplification of 700 to 1003 base pairs (bp) for PKC α(GenBank accession number X52479), 914 to 1399 bp for PKC β (GenBankaccession number X06318), 1506 to 1823 bp for PKC γ (GenBank accessionnumber AF345987), and 295 to 675 bp for NSE (GenBank accession number X14327).The internal primers for PKC isozymes and NSE were as follows: PKC α,843 to 866 bp; PKC β, 1131 to 1155 bp; PKC γ, 1645 to 1668 bp;and NSE, 403 to 423 bp. Internal standards contained Bg1II (PKC isozymes) or XhoI (NSE) restrictionendonuclease sites. Decreasing concentrations of PKC isozyme or NSE internalstandard complementary RNAs were added to 1 µg of total RNA. The polymerasechain reaction mixture was amplified for 30 cycles, digested with Bg1II or with XhoI in triplicate, and runon 1.5% agarose gel. The results were calculated as the counts incorporatedinto the amplified complementary RNA standard divided by the counts incorporatedinto the corresponding mRNA amplification product vs the known amount of PKCisozyme or NSE internal standard added to the test sample. The results areexpressed as attomoles per microgram of total RNA.

STATISTICAL ANALYSIS

Data analyses were performed using a statistical software package (SPSS8.0; SPSS Inc, Chicago, Ill). All values are reported as mean ± SD.Differences in PKC catalytic activity, mRNA and protein levels of PKC isozymes,age, sex, postmortem interval (PMI), and pH of the brain between suicide victimsand control subjects were analyzed using the independent-sample t test. The relationships between PKC catalytic activity, mRNA andprotein levels of PKC isozymes, PMI, age, sex, and pH of the brain were determinedby using Pearson product moment correlation analysis. P values were 2-tailed. Statistical differences between subgroups ofsuicide victims (with and without mental disorders) and controls were evaluatedby using 1-way analysis of variance. During analysis of the data, we includedrace as a potential confounding variable.

The detailed demographic characteristics of the teenage suicide victims(n = 17) and the control subjects (n = 17) are given in Table 1. There were no significant differences in age (t32 = 1.5; P = .12), PMI (t31 = 0.84; P = .40),or pH of the brain (t32 = 0.51; P = .61) between controls and suicide victims.

Protein kinase C activity was determined in membrane and cytosol fractionsof the PFC and hippocampus (Figure 1).There was a significant decrease in PKC activity in membrane and cytosol fractionsof the PFC and hippocampus of teenage suicide victims compared with controlsubjects (PFC: membrane, t32 = 4.65; P<.001; cytosol, t32 =3.59; P = .001; and hippocampus: membrane, t32 = 3.2; P = .003;cytosol, t32 = 2.77; P = .009).

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Figure 1.

Mean protein kinase C (PKC) catalyticactivity in membrane and cytosol fractions of the prefrontal cortex (A) andhippocampus (B) obtained from 17 control subjects and 17 teenage suicide victims.Error bars represent SD. Asterisk indicates P<.001;dagger, P = .002.

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Figure 2 shows representativeimmunoblots of the various PKC isozymes in membrane and cytosol fractionsobtained from the PFC of 2 teenage suicide victims and 2 control subjects.Protein kinase C α, βI, βII, and γ isozymes migratedto 80 kDa, whereas β-actin migrated to 46 kDa. Levels of PKC α, βI, βII,and γ decreased in membrane and cytosol fractions obtained from thePFC of teenage suicide victims. Mean levels of PKC α, βI, βII,and γ were significantly decreased in membrane and cytosol fractionsof the PFC (Figure 3) and hippocampus(Figure 4) of teenage suicide victimscompared with controls. The significance levels of these decreases in thePFC were as follows: membrane—PKC α, t32 = 4.6; P<.001; PKC βI, t32 = 4.1; P<.001; PKC βII, t32 = 4.5; P<.001;and PKC γ, t32 = 3.3; P = .002; cytosol—PKC α, t32 = 3.5; P = .001; PKC βI, t32 = 4.1; P<.001; PKC βII, t32 = 3.8; P = .001;and PKC γ, t32 = 6.3; P<.001. The significance levels of these decreases in the hippocampuswere as follows: membrane—PKC α, t32 = 3.2; P = .003; PKC βI, t32 = 3.8; P<.001; PKC βII, t32 = 2.6; P = .02;and PKC γ, t32 = 3.1; P = .004; cytosol—PKC α, t2.032 = 2.8; P = .009; PKC βI, t32 = 3.9; P<.001; PKC βII, t32 = 2.0; P = .04;and PKC γ, t32 = 2.4; P = .02.

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Figure 2.

Representative Western blots showingthe immunolabeling of protein kinase C (PKC) isozymes (PKC α, β,and γ) in membrane and cytosol fractions from the prefrontal cortexof 2 control subjects and 2 suicide victims. Protein samples were subjectedto 10% polyacrylamide gel electrophoresis and transferred to chemiluminescencemembranes, which were then incubated with primary antibodies specific foreach PKC isozyme and secondary anti–rabbit antibody. The membranes werestriped and probed with primary β-actin and secondary anti–mouseantibody. The bands were quantified as described in the "Methods" section.Ratios of the optical densities of PKC isozymes to that of β-actin werecalculated.

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Figure 3.

Mean protein levels of proteinkinase C (PKC) α, βI, βII, and γ isozymes in membrane(A) and cytosol (B) fractions of the prefrontal cortex obtained from 17 teenagesuicide victims and 17 control subjects. Error bars represent SD. Asteriskindicates P = .001; dagger, P<.001;and double dagger, P = .002.

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Figure 4.

Mean protein levels of proteinkinase C (PKC) α, βI, βII, and γ isozymes in membrane(A) and cytosol (B) fractions of the hippocampus obtained from 17 teenagesuicide victims and 17 control subjects. Error bars represent SD. Asteriskindicates P = .003; dagger, P =.001; double dagger, P = .02; section mark, P = .004, parallel mark, P = .009;paragraph symbol, P<.001; and number sign, P = .04.

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To examine whether decreases in PKC isozyme levels were related to alteredtranscription of their respective mRNAs, we determined the mRNA levels ofthe various PKC isozymes by using quantitative reverse transcriptase–polymerasechain reaction (RT-PCR). Representative gel electrophoreses of the competitiveRT-PCR of PKC isozymes are shown in Figure5A-C for 1 control subject. The results of a competitive RT-PCRanalysis for PKC α, β, and γ are shown in Figure 5D-F, where the point of equivalence represents the amountof PKC isozyme mRNAs present. The mRNA levels of PKC α, β, and γwere significantly decreased in the PFC (PKC α, t30 = 5.5; P<.001; PKC β, t30 = 3.3; P = .002;and PKC γ, t30 = 3.7; P = .001) and in the hippocampus (PKC α, t30 = 5.5; P<.001; PKC β, t30 = 3.3; P = .002;and PKC γ, t30 = 3.7; P = .001) of teenage suicide victims (Figure 6). To establish whether neuronal RNA contributes equallyto the total RNA pool, we determined the mRNA level of NSE in the PFC of suicidevictims and control subjects. Levels of NSE mRNA in PFC in control subjectsvs suicide victims showed no significant differences (360 ± 89 vs 408± 98 attomoles/µg of total RNA; t30 = 1.46; P = .15). However, the ratios ofPKC isozyme to NSE mRNA showed that PKC mRNA levels were significantly decreasedin the PFC of suicide victims when expressed as a function of NSE mRNA (PKC α:control, 0.26 ± 0.11; suicide, 0.11 ± 0.04; PKC β: control,0.46 ± 0.32; suicide, 0.15 ± 0.08; and PKC γ: control,1.2 ± 0.22; suicide, 0.69 ± 0.20).

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Figure 5.

A representative experiment showinga competitive polymerase chain reaction analysis for protein kinase C (PKC) α(A), PKC β (B), and PKC γ (C) messenger RNA (mRNA) contents inthe prefrontal cortex of 1 control subject. Decreasing concentrations of complementaryRNA (cRNA) for PKC α (100-6.25 pg), PKC β (200-6.25 pg), or PKC γ(400-12.5 pg) were added to a constant amount (1 µg) of total RNA. Themixtures were reverse transcribed and polymerase chain reaction amplifiedin the presence of trace amounts of [32P]dCTP (cytidine triphosphate);aliquots were digested by Xho I and electrophoresedon 1.5% agarose gel. The higher molecular size band corresponds to amplificationproduct arising from the mRNA, whereas the lower band arises from cRNA generatedfrom the internal standard digested by Xho I. Dataderived from the agarose gel are plotted as the counts incorporated into theamplified cRNA standard divided by the counts incorporated into the correspondingPKC α (D), PKC β (E), or PKC γ (F) mRNA amplification productvs the known amount of internal standard cRNA added to the test sample. Thepoint of equivalence represents the amount of the respective mRNA.

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Figure 6.

Mean messenger RNA (mRNA) levelsof protein kinase C (PKC) α, β, and γ in the prefrontal cortex(A) and hippocampus (B) of 17 control subjects and 15 teenage suicide victims.Error bars represent SD. Asterisk indicates P<.001;dagger, P = .002; double dagger, P = .001.

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EFFECT OF CONFOUNDING VARIABLES AND DIAGNOSIS

We did not find any effect of age, PMI, and pH of the brain on any ofthe PKC measures in either the PFC or the hippocampus (data not shown). Inaddition, we examined whether antidepressant drug treatment affects any ofthe measures. Of 17 suicide victims, 3 had toxicologic evidence of antidepressantdrugs. Comparison of suicide victims with toxicologic findings positive forantidepressant drugs with those without such findings revealed no significantdifferences in PKC activity or in protein and mRNA levels of PKC isozymesin the PFC and hippocampus between these 2 groups (data not shown).

Some previous studies24 have shown anassociation between abnormalities in PKC activity and PKC isozymes in theplatelets of patients with mood disorders. We, therefore, examined whetherthe decrease in PKC isozyme levels is associated with mental disorders orwhether it is associated with suicide independent of diagnosis. Of the 17suicide victims, 9 had a history of some kind of mental disorder, primarilymood disorders and adjustment disorders, and 8 had no history of mental disorders,although 2 had a history of alcohol or other drug abuse. When we comparedthe various PKC isozymes between patients who had a lifetime history of mentaldisorder and those who did not have such a history, there were no statisticallysignificant differences between the 2 groups in catalytic activity of PKCor in protein expression of any of the PKC isozymes in membrane and cytosolfractions. Similarly, there were no significant differences in mRNA expressionlevels in patients who had a lifetime history of mental disorders and thosewho did not have such a history; however, both subgroups were significantlylower than control subjects in terms of protein and mRNA expression of thevarious PKC isozymes (data not shown). These results thus suggest that thedecreases in protein and mRNA expression of PKC isozymes found in teenagesuicide victims were independent of diagnosis.

EFFECT OF SEX ON PKC ACTIVITY AND ON PROTEIN AND mRNA LEVELS OF PKCISOZYMES

There were 16 males and 1 female in the control group and 10 males and7 females in the suicide group. To examine whether the uneven sex distributionhad any effects on PKC, we analyzed the data in males in the control and suicidegroups. We found significant differences in PKC activity (PFC: membrane, t24 = 3.08; P = .01;cytosol, t24 = 4.2 P<.001; and hippocampus: membrane, t24 = 2.4; P = .02; cytosol, t24 = 4.04; P = .001), proteinlevels (PFC—membrane: PKC α, t24 = 3.9; P = .001; PKC β, t24 = 4.2; P<.001; and PKC γ, t24 = 2.7; P = .01;and cytosol: PKC α, t24 = 2.6; P = .01; PKC β, t24 = 4.7; P = .001; and PKC γ, t24 = 5.4; P<.001; and hippocampus—membrane:PKC α, t24 = 2.6; P = .01; PKC β, t24 = 3.4; P = .005; and PKC γ, t24 = 2.4; P = .02; and cytosol: PKC α, t24 = 2.0; P = .05;PKC β, t24 = 3.5; P = .002; and PKC γ, t24 =2.2; P = .03), and mRNA levels (PFC: PKC α, t22 = 3.5; P = .002;PKC β, t22 = 2.4; P = .02; and PKC γ, t22 =2.2; P = .03; and hippocampus: PKC α, t22 = 3.5; P = .002;PKC β, t22 = 2.4; P = .02; and PKC γ, t22 =2.6; P = .01) between controls and suicide victimswith a similar magnitude as observed after inclusion of females. In the suicidegroup, we also analyzed the data comparing male and female suicide victims.We did not find any significant effects of sex on PKC activity or mRNA andprotein levels of PKC isozymes (data not shown). These data suggest that theeffects seen on PKC are not related to sex.

Because there was an uneven distribution of race between the controland suicide groups, we analyzed the effect of race by comparing PKC measuresbetween blacks and whites in both groups and found no significant differencesbetween them (data not shown). We also included race as a covariate in theanalysis.

The results of the present study reveal a statistically significantreduction in the catalytic activity of PKC in the PFC and hippocampus of teenagesuicide victims compared with control subjects. This reduction in PKC activitywas associated with decreases in protein and mRNA expression of PKC α, β,and γ isozymes in the PFC and hippocampus of teenage suicide victims.These changes were not related to age, PMI, or pH of the brain. Furthermore,these changes were not associated with mental disorders, as no statisticallysignificant differences were observed either in PKC activity or in proteinor mRNA expression of PKC α, β, and γ isozymes between suicidevictims with no history of mental disorders and those with a history of mentaldisorders in either the PFC or the hippocampus. However, PKC activity andprotein and mRNA expression of the PKC isozymes in suicide victims with orwithout mental disorders still were statistically significantly lower thanin control subjects. This observation has provided preliminary evidence suggestingthat alterations in PKC activity and isozymes in teenage suicide victims areindependent of diagnosis. However, these results need to be replicated ina larger number of suicide victims with or without mental disorders beforearriving at a definite conclusion on the effect of mental disorders on PKCisozymes.

There is direct and indirect evidence suggesting that PKC may play animportant role in the pathogenesis of mood disorders. Indirect evidence isderived from the observations that treatment with lithium and other mood-stabilizingdrugs causes a decrease in PKC activity and expression of certain PKC isozymesin rat brain.32 Because this effect of lithiumis also shared by other mood-stabilizing drugs, such as valproate,32 this implies that a PKC abnormality may be associatedwith bipolar illness and that treatment with lithium or other mood-stabilizingdrugs may normalize this abnormality. Direct evidence in support of the involvementof PKC in mood disorders is limited and is derived mainly from studies ofPKC in platelets obtained from patients with mood disorders. For example,a previous study23 reported that PKC activityis decreased in platelets of bipolar patients compared with control subjects.This decrease in PKC activity was mainly due to a selective decrease in theprotein expression of PKC α, βI, βII, and δ in membraneand cytosol fractions of platelets from bipolar patients. Friedman et al24 and Young et al33 reportedthat PKC activity is increased in platelets of bipolar patients during themanic phase. Young et al33 studied the expressionof PKC α in these patients and did not find any difference in cytosoland membrane fractions of platelets obtained from bipolar patients.

Protein kinase C has not been studied extensively in the postmortembrain. In a recent study, Pandey et al25 determinedPKC binding sites using [3H]PDBu, which is a measure of the regulatorybinding site of PKC, in the PFC of teenage suicide victims and nonpsychiatriccontrol subjects and found that [3H]PDBu binding was significantlydecreased in teenage suicide victims compared with control subjects. Coullet al34 also studied [3H]PBDu bindingin the PFC and hippocampus of antidepressant-treated and antidepressant-freeadult depressed suicide victims. They did not find any significant differencesin [3H]PBDu binding between antidepressant-treated suicide victimsand control subjects. On the other hand, they found a significant increasein the Bmax of [3H]PDBu binding in the soluble fractionsof antidepressant-free suicide victims compared with control subjects. Theapparent differences between our study and that of the depressed suicide victimsreported by Coull et al34 could be due to thedifference in age of the populations studied. It is possible that the changesin PKC may be different in teenage vs adult suicide victims because of developmentalfactors and factors associated with chronicity of illness or previous long-termtreatment with psychoactive drugs. Dean et al35 reporteda significant decrease in the density of PKC in the parahippocampal gyrusof patients with schizophrenia compared with control subjects. The resultsof studies of PKC in postmortem brain thus seem to be mixed; however, almostall studies in the postmortem brain of suicide victims, patients with schizophrenia,or depressed suicide victims were carried out using [3H]PDBu forlabeling PKC binding sites, but none of these studies examined the proteinor mRNA expression of individual PKC isozymes. Although [3H]PDBuhas been used for studying PKC binding sites, it is believed that [3H]PDBu also labels other proteins, such as α-chimaerins and RAS-GRP,and it is possible that the failure to find any changes in PKC binding sitesmay not reflect abnormal expression of PKC protein. Studies of PKC activityand of expression of the various PKC isozymes may, therefore, be importantin examining the role of PKC in these disorders. To our knowledge, this isthe first study to examine protein and mRNA expression and PKC activity inpostmortem brains obtained from psychiatric patients and suicide victims.As mentioned earlier herein, we found that the expression of 3 different PKCisozymes—PKC α, β, and γ—was significantly decreasedin the PFC and hippocampus of teenage suicide victims.

The mechanism by which PKC is decreased in the postmortem brain of suicidevictims is not clear. The activation of PKC by an agonist such as diacylglycerolor phorbol myristate acetate causes the translocation of PKC from the cytosolto the membrane. This translocation also facilitates the proteolytic degradationof the enzyme. Another possibility could be related to a compensatory mechanismin response to the sustained activation of the receptors to which this signalingcascade is linked. For example, our group5 recentlyreported that 5-HT2A receptors are increased in the postmortembrain of teenage suicide victims. It is possible that activation of theseincreased receptors may cause continued activation of the enzyme and the down-regulationof PKC and some of its specific isozymes. That this mechanism may be a reasonfor the decrease in PKC in the postmortem brain of suicide victims is supportedby the observation of some investigators that continued activation of theenzyme PKC by phorbol esters causes its translocation and subsequent degradationand decrease.36 The other reason for a possibledecrease in PKC may be related to an overactive hypothalamic-pituitary-adrenal(HPA) axis in suicide. It has been reported that the HPA axis may be abnormalin suicide victims.37 Earlier, our group38 showed that activation of the HPA axis causes down-regulationof certain PKC isozymes in rat brain. Therefore, it is possible that the changesin PKC may be related to altered HPA function in suicide victims.

The pathophysiologic significance of the decrease in PKC in suicidevictims remains to be elucidated; however, the phosphorylation of proteins,mediated by PKC, is a key to many physiologic functions in the brain, includinggene transcription. Some examples of proteins phosphorylated by PKC are MARCKSand GPA-43. Both these proteins have been implicated in mood disorders.23,32 Furthermore, certain evidence indicatesthat besides phosphorylating proteins in cytosol, PKC α, β, and γtranslocate into the nucleus and phosphorylate many nuclear proteins,39,40 cell cycle–related proteins,41 and transcription factors, such as CREB and NFκB.42,43 Although specific functions of eachPKC isozyme are not clearly known, recent studies demonstrate that PKC αis closely associated with proliferation, cell differentiation, and metabolismand with some cell type–specific functions, such as β-cell developmentand activation.44,45 As far asPKC γ is concerned, it is the only PKC isozyme that is present solelyin the brain and spinal cord.16,46 Manyneuronal functions have been attributed to PKC γ, among them synapticformation, long-term potentiation, long-term depression, and modulation ofreceptor functions, particularly γ-aminobutyric acid A.47 Proteinkinase C γ–deficient mice exhibit impaired motor coordinationand deficits in spatial and contextual learning.48 Mutationin PKC γ also shows brain pathology resembling the parkinsonian syndrome.49,50 Whether a deficiency in PKC is associatedwith suicidal behavior is not clearly known; however, given the many substratesthat PKC phosphorylates, a deficiency in PKC isozymes may disrupt normal brainfunction.

Regardless of the mechanism by which PKC is down-regulated in the postmortembrain of suicide victims, our observation that PKC activity and some of itsisozymes are decreased in the postmortem brain of teenage suicide victimsmay be vitally important in understanding the neurobiologic abnormalitiesof suicide.

Correspondence: Ghanshyam N. Pandey, PhD, Psychiatric Institute,Department of Psychiatry, University of Illinois at Chicago, 1601 W TaylorSt, Chicago, IL 60612 (Gnpandey@psych.uic.edu)

Submitted for publication July 11, 2003; final revision received January27, 2004; accepted February 3, 2004.

This work was supported by grants RO1 MH 48153 (Dr Pandey) and KO1 MH01836 (Dr Dwivedi) from the National Institute of Mental Health, Rockville,Md, and by the American Foundation for Suicide Prevention, New York, NY (DrDwivedi).

We thank Dr Smialek, MD, chief medical examiner, and Dennis Chute, MD,assistant medical examiner, for their cooperation in the collection of brainsamples; Terri U'Prichard, MA, for performing the psychological autopsies;and Barbara Brown, BS, and Miljana Petkovic, BS, for their help in organizingthe brain tissue.

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Pandey  GNDwivedi  YRizavi  HSRen  XPandey  SCPesold  CRoberts  RCConley  RRTamminga  CA Higher expression of serotonin 5HT2A receptors in the postmortem brainsof teenage suicide victims. Am J Psychiatry. 2002;159419- 429
PubMed
Pacheco  MAStockmeier  CMeltzer  HYOverholser  JCDilley  GEJope  RS Alterations in phosphoinositide signaling and G-protein levels in depressedsuicide brain. Brain Res. 1996;72337- 45
PubMed
Dwivedi  YRao  JSRizavi  HSKotowski  JConley  RRRoberts  RCTamminga  CAPandey  GN Abnormal expression and functional characteristics of cyclic adenosinemonophosphate response element binding protein in postmortem brain of suicidesubjects. Arch Gen Psychiatry. 2003;60273- 282
PubMed
Dwivedi  YRizavi  HSConley  RRRoberts  RCTamminga  CAPandey  GN mRNA and protein expression of selective α subunits of G proteinare abnormal in prefrontal cortex of suicide victims. Neuropsychopharmacology. 2002;27499- 517
PubMed
Jope  RSSong  LGrimes  CAPacheco  MADilley  GELi  XMeltzer  HYOverholser  JCStockmeier  CA Selective increases in phosphoinositide signaling activity and G proteinlevels in postmortem brain from subjects with schizophrenia or alcohol dependence. J Neurochem. 1998;70763- 771
PubMed
Apter  AGothelf  DOrbach  IWeizman  RRatzoni  GHar-Even  DTyano  S Correlation of suicidal and violent behavior in different diagnosticcategories in hospitalized adolescent patients. J Am Acad Child Adolesc Psychiatry. 1995;34912- 918
PubMed
Brent  DKolko  DWartella  MBoylan  MMoritz  GBaugher  MZelenak  J Adolescent psychiatric inpatients' risk of suicide attempt at 6-monthfollow-up. J Am Acad Child Adolesc Psychiatry. 1993;3295- 105
PubMed
Linnoila  VMVirkkunen  M Aggression, suicidality, and serotonin. J Clin Psychiatry. 1992;5346- 51
PubMed
Nishizuka  Y The molecular heterogeneity of protein kinase C and its implicationsfor cellular regulation. Nature. 1988;334661- 665
PubMed
Nishizuka  Y Intracellular signaling by hydrolysis of phospholipids and activationof protein kinase C. Science. 1992;258607- 613
PubMed
Berridge  MJIrvine  RF Inositol phosphates and cell signaling. Nature. 1989;341197- 205
PubMed
Tanaka  CNishizuka  Y The protein kinase C family for neuronal signaling. Annu Rev Neurosci. 1994;17551- 567
PubMed
Olds  JLAlkon  DL A role for protein kinase C in associative learning. New Biol. 1991;327- 35
PubMed
Shearman  MSSekiguchi  KNishizuka  Y Modulation of ion channel activity: a key function of the protein kinaseC enzyme family. Pharmacol Rev. 1989;41211- 237
PubMed
Dempsey  ECNewton  ACMochly-Rosen  DFields  APReyland  MEInsel  PAMessing  RO Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol. 2000;279L429- L438
PubMed
Manji  HKBebchuk  JMMoore  GJGlitz  DHasanat  KAChen  G Modulation of CNS signal transduction pathways and gene expressionby mood-stabilizing agents: therapeutic implications. J Clin Psychiatry. 1999;6027- 39
PubMed
Barr  LFCampbell  SEBaylin  SB Protein kinase C-β 2 inhibits cycling and decreases c-myc–inducedapoptosis in small cell lung cancer cells. Cell Growth Differ. 1997;8381- 392
PubMed
Shigeo  ONishizuka  Y Protein kinase C isotypes and their specific functions: prologue. J Biochem (Tokyo). 2002;132509- 511
PubMed
Pandey  GNDwivedi  YSridharaRao  JRen  XJanicak  PGSharma  R Protein kinase C and phospholipase C activity and expression of theirspecific isozymes is decreased and expression of MARCKS is increased in plateletsof bipolar but not in unipolar patients. Neuropsychopharmacology. 2002;26216- 228
PubMed
Friedman  EWang  H-YLevinson  DConnell  TASingh  H Altered platelet protein kinase C activity in bipolar affective disorder,manic episode. Biol Psychiatry. 1993;33520- 525
PubMed
Pandey  GNDwivedi  YPandey  SCConley  RRRoberts  RCTamminga  CA Protein kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett. 1997;228111- 114
PubMed
Worley  PFBaraban  JMSnyder  SH Heterogenous localization of protein kinase C in rat brain: autoradiographicanalysis of phorbol ester receptor binding. J Neurosci. 1986;6199- 207
PubMed
Olds  JLGolski  SMcPhie  DLOlton  DMishkin  MAlkon  DL Discrimination learning alters the distribution of protein kinase Cin the hippocampus of rats. J Neurosci. 1990;103707- 3713
PubMed
Salzman  SEndicott  JClayton  PWinouker  G Diagnostic Evaluation After Death (DEAD).  Rockville, Md Neuroscience Research Branch, National Institute ofMental Health1983;
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R (SCID),I: history, rationale, and description. Arch Gen Psychiatry. 1992;49624- 629
PubMed
Dwivedi  YPandey  GN Administration of dexamethasone upregulates protein kinase C activityand the expression of γ and ϵ protein kinase C isozymes in therat brain. J Neurochem. 1999;72380- 387
PubMed
Dwivedi  YPandey  GN Quantitation of 5HT2A receptor mRNA in human postmortem brain usingcompetitive RT-PCR. Neuroreport. 1998;93761- 3765
PubMed
Manji  HKMoore  GJChen  G Clinical and preclinical evidence for the neurotrophic effects of moodstabilizers: implications for the pathophysiology and treatment of manic-depressiveillness. Biol Psychiatry. 2000;48740- 754
PubMed
Young  LTWang  JFWoods  CMRobb  JC Platelet protein kinase C α levels in drug-free and lithium-treatedsubjects with bipolar disorder. Neuropsychobiology. 1999;4063- 66
PubMed
Coull  MALowther  SKatona  CLEHorton  RW Altered brain protein kinase C in depression: a postmortem study. Eur Neuropsychopharmacol. 2000;10283- 288
PubMed
Dean  BOpeskin  KPavey  GHill  CKeks  N Changes in protein kinase C and adenylate cyclase in the temporal lobefrom subjects with schizophrenia. J Neural Transm. 1997;1041371- 1381
PubMed
Manji  HKLenox  RH Protein kinase C signaling in the brain: molecular transduction ofmood stabilization in the treatment of manic depressive illness. Biol Psychiatry. 1999;461328- 1351
PubMed
Lopez  JFPalkovits  MArato  MMansour  AAkil  HWatson  SJ Localization and quantification of pro-opiomelanocortin mRNA and glucocorticoidreceptor mRNA in pituitaries of suicide victims. Neuroendocrinology. 1992;56491- 501
PubMed
Pandey  GNDwivedi  Y Effects of adrenal glucocorticoids on protein kinase C (PKC) bindingsites, PKC activity and expression of PKC isozymes in the rat brain. J Neurochem. 2000;74S21D
Banks  GCLi  YReeves  R Differential in vivo modifications of the HMGI(Y) monohistone chromatinproteins modulate nucleosome and DNA interactions. Biochemistry. 2000;398333- 8346
PubMed
Hocevar  BABurns  DJFields  AP Identification of protein kinase C (PKC) phosphorylation sites on humanlamin B: potential role of PKC in nuclear lamina structural dynamics. J Biol Chem. 1993;2687545- 7552
PubMed
Frey  MRClark  JALeontieva  OUronis  JMBlack  ARBack  JD Protein kinase C signaling mediates a program of cell cycle withdrawalin the intestinal epithelium. J Cell Biol. 2000;151763- 778
PubMed
Vertegaal  ACKuiperij  HBYamaoka  SCourtois  Gvan der Eb  MZantema  A Protein kinase C-α is an upstream activator of the IκBkinase complex in the TPA signal transduction pathway to NF-κB in U2OScells. Cell Signal. 2000;12759- 768
PubMed
Yuan  LWGambee  JE Phosphorylation of p300 at serine 89 by protein kinase C. J Biol Chem. 2000;27540946- 40951
PubMed
Nakashima  S Protein kinase Cα (PKCα): regulation and biological function. J Biochem (Tokyo). 2002;132669- 675
PubMed
Leitges  MSchmedt  CGuinamard  RDavoust  JSchaal  SStabel  STarakhovsky  A Immunodeficiency in protein kinase Cβ–deficient mice. Science. 1996;273768- 791
PubMed
Saito  NKikkawa  UNishizuka  YTanaka  C Distribution of protein kinase C–like immunoreactive neuronsin rat brain. J Neurosci. 1988;8369- 382
PubMed
Saito  NShirai  Y Protein kinase Cγ (PKCγ): function of neuron specific isotype. J Biochem (Tokyo). 2002;132683- 687
PubMed
Kano  MHashimoto  KChen  CAbeliovich  AAiba  AKurihara  HWatanabe  MInoue  YTonegawa  S Impaired synapse elimination during cerebellar development in PKCγmutant mice. Cell. 1995;831223- 1231
PubMed
Campbell  JMPayne  APGilmore  DPRussel  DMcGadey  JClarke  DJBranton  RDavies  RWSutcliffe  RG Age change in dopamine levels in the corpus striatum of Albino Swiss(AS) and AS/AGU mutant mice. Neurosci Lett. 1997;23954- 56
PubMed
Payne  APCampbell  JMRussel  DFavor  GSutcliffe  RGBennet  NKDavies  RWStone  TW The AS/AGU rat: a spontaneous model of disruption of degeneration inthe nigrostriatal dopaminergic system. J Anat. 2000;196629- 633
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Mean protein kinase C (PKC) catalyticactivity in membrane and cytosol fractions of the prefrontal cortex (A) andhippocampus (B) obtained from 17 control subjects and 17 teenage suicide victims.Error bars represent SD. Asterisk indicates P<.001;dagger, P = .002.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Representative Western blots showingthe immunolabeling of protein kinase C (PKC) isozymes (PKC α, β,and γ) in membrane and cytosol fractions from the prefrontal cortexof 2 control subjects and 2 suicide victims. Protein samples were subjectedto 10% polyacrylamide gel electrophoresis and transferred to chemiluminescencemembranes, which were then incubated with primary antibodies specific foreach PKC isozyme and secondary anti–rabbit antibody. The membranes werestriped and probed with primary β-actin and secondary anti–mouseantibody. The bands were quantified as described in the "Methods" section.Ratios of the optical densities of PKC isozymes to that of β-actin werecalculated.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Mean protein levels of proteinkinase C (PKC) α, βI, βII, and γ isozymes in membrane(A) and cytosol (B) fractions of the prefrontal cortex obtained from 17 teenagesuicide victims and 17 control subjects. Error bars represent SD. Asteriskindicates P = .001; dagger, P<.001;and double dagger, P = .002.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Mean protein levels of proteinkinase C (PKC) α, βI, βII, and γ isozymes in membrane(A) and cytosol (B) fractions of the hippocampus obtained from 17 teenagesuicide victims and 17 control subjects. Error bars represent SD. Asteriskindicates P = .003; dagger, P =.001; double dagger, P = .02; section mark, P = .004, parallel mark, P = .009;paragraph symbol, P<.001; and number sign, P = .04.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

A representative experiment showinga competitive polymerase chain reaction analysis for protein kinase C (PKC) α(A), PKC β (B), and PKC γ (C) messenger RNA (mRNA) contents inthe prefrontal cortex of 1 control subject. Decreasing concentrations of complementaryRNA (cRNA) for PKC α (100-6.25 pg), PKC β (200-6.25 pg), or PKC γ(400-12.5 pg) were added to a constant amount (1 µg) of total RNA. Themixtures were reverse transcribed and polymerase chain reaction amplifiedin the presence of trace amounts of [32P]dCTP (cytidine triphosphate);aliquots were digested by Xho I and electrophoresedon 1.5% agarose gel. The higher molecular size band corresponds to amplificationproduct arising from the mRNA, whereas the lower band arises from cRNA generatedfrom the internal standard digested by Xho I. Dataderived from the agarose gel are plotted as the counts incorporated into theamplified cRNA standard divided by the counts incorporated into the correspondingPKC α (D), PKC β (E), or PKC γ (F) mRNA amplification productvs the known amount of internal standard cRNA added to the test sample. Thepoint of equivalence represents the amount of the respective mRNA.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

Mean messenger RNA (mRNA) levelsof protein kinase C (PKC) α, β, and γ in the prefrontal cortex(A) and hippocampus (B) of 17 control subjects and 15 teenage suicide victims.Error bars represent SD. Asterisk indicates P<.001;dagger, P = .002; double dagger, P = .001.

Graphic Jump Location

Tables

Table Graphic Jump LocationDemographic, Clinical, and Toxicologic Characteristics of 17 TeenageSuicide Victims and 17 Control Subjects

References

Moscicki  EKO'Carroll  PRae  DSLocke  BZRoy  ARegier  DA Suicide attempts in the Epidemiologic Catchment Area Study. Yale J Biol Med. 1988;61259- 268
PubMed
Minino  AMSmith  BL Deaths: preliminary data for 2000. Natl Vital Stat Rep. 2001;491- 40
PubMed
Botsis  AFSoldatos  CRStefanis  CN Suicide: Biopsychosocial Approaches.  Amsterdam, the Netherlands Elsevier Science Publishers1997;
Gross-Isseroff  RBiegon  AVoet  HWeizman  A The suicide brain: a review of postmortem receptor/transporter bindingstudies. Neurosci Biobehav Rev. 1998;22653- 661
PubMed
Pandey  GNDwivedi  YRizavi  HSRen  XPandey  SCPesold  CRoberts  RCConley  RRTamminga  CA Higher expression of serotonin 5HT2A receptors in the postmortem brainsof teenage suicide victims. Am J Psychiatry. 2002;159419- 429
PubMed
Pacheco  MAStockmeier  CMeltzer  HYOverholser  JCDilley  GEJope  RS Alterations in phosphoinositide signaling and G-protein levels in depressedsuicide brain. Brain Res. 1996;72337- 45
PubMed
Dwivedi  YRao  JSRizavi  HSKotowski  JConley  RRRoberts  RCTamminga  CAPandey  GN Abnormal expression and functional characteristics of cyclic adenosinemonophosphate response element binding protein in postmortem brain of suicidesubjects. Arch Gen Psychiatry. 2003;60273- 282
PubMed
Dwivedi  YRizavi  HSConley  RRRoberts  RCTamminga  CAPandey  GN mRNA and protein expression of selective α subunits of G proteinare abnormal in prefrontal cortex of suicide victims. Neuropsychopharmacology. 2002;27499- 517
PubMed
Jope  RSSong  LGrimes  CAPacheco  MADilley  GELi  XMeltzer  HYOverholser  JCStockmeier  CA Selective increases in phosphoinositide signaling activity and G proteinlevels in postmortem brain from subjects with schizophrenia or alcohol dependence. J Neurochem. 1998;70763- 771
PubMed
Apter  AGothelf  DOrbach  IWeizman  RRatzoni  GHar-Even  DTyano  S Correlation of suicidal and violent behavior in different diagnosticcategories in hospitalized adolescent patients. J Am Acad Child Adolesc Psychiatry. 1995;34912- 918
PubMed
Brent  DKolko  DWartella  MBoylan  MMoritz  GBaugher  MZelenak  J Adolescent psychiatric inpatients' risk of suicide attempt at 6-monthfollow-up. J Am Acad Child Adolesc Psychiatry. 1993;3295- 105
PubMed
Linnoila  VMVirkkunen  M Aggression, suicidality, and serotonin. J Clin Psychiatry. 1992;5346- 51
PubMed
Nishizuka  Y The molecular heterogeneity of protein kinase C and its implicationsfor cellular regulation. Nature. 1988;334661- 665
PubMed
Nishizuka  Y Intracellular signaling by hydrolysis of phospholipids and activationof protein kinase C. Science. 1992;258607- 613
PubMed
Berridge  MJIrvine  RF Inositol phosphates and cell signaling. Nature. 1989;341197- 205
PubMed
Tanaka  CNishizuka  Y The protein kinase C family for neuronal signaling. Annu Rev Neurosci. 1994;17551- 567
PubMed
Olds  JLAlkon  DL A role for protein kinase C in associative learning. New Biol. 1991;327- 35
PubMed
Shearman  MSSekiguchi  KNishizuka  Y Modulation of ion channel activity: a key function of the protein kinaseC enzyme family. Pharmacol Rev. 1989;41211- 237
PubMed
Dempsey  ECNewton  ACMochly-Rosen  DFields  APReyland  MEInsel  PAMessing  RO Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol. 2000;279L429- L438
PubMed
Manji  HKBebchuk  JMMoore  GJGlitz  DHasanat  KAChen  G Modulation of CNS signal transduction pathways and gene expressionby mood-stabilizing agents: therapeutic implications. J Clin Psychiatry. 1999;6027- 39
PubMed
Barr  LFCampbell  SEBaylin  SB Protein kinase C-β 2 inhibits cycling and decreases c-myc–inducedapoptosis in small cell lung cancer cells. Cell Growth Differ. 1997;8381- 392
PubMed
Shigeo  ONishizuka  Y Protein kinase C isotypes and their specific functions: prologue. J Biochem (Tokyo). 2002;132509- 511
PubMed
Pandey  GNDwivedi  YSridharaRao  JRen  XJanicak  PGSharma  R Protein kinase C and phospholipase C activity and expression of theirspecific isozymes is decreased and expression of MARCKS is increased in plateletsof bipolar but not in unipolar patients. Neuropsychopharmacology. 2002;26216- 228
PubMed
Friedman  EWang  H-YLevinson  DConnell  TASingh  H Altered platelet protein kinase C activity in bipolar affective disorder,manic episode. Biol Psychiatry. 1993;33520- 525
PubMed
Pandey  GNDwivedi  YPandey  SCConley  RRRoberts  RCTamminga  CA Protein kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett. 1997;228111- 114
PubMed
Worley  PFBaraban  JMSnyder  SH Heterogenous localization of protein kinase C in rat brain: autoradiographicanalysis of phorbol ester receptor binding. J Neurosci. 1986;6199- 207
PubMed
Olds  JLGolski  SMcPhie  DLOlton  DMishkin  MAlkon  DL Discrimination learning alters the distribution of protein kinase Cin the hippocampus of rats. J Neurosci. 1990;103707- 3713
PubMed
Salzman  SEndicott  JClayton  PWinouker  G Diagnostic Evaluation After Death (DEAD).  Rockville, Md Neuroscience Research Branch, National Institute ofMental Health1983;
Spitzer  RLWilliams  JBWGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R (SCID),I: history, rationale, and description. Arch Gen Psychiatry. 1992;49624- 629
PubMed
Dwivedi  YPandey  GN Administration of dexamethasone upregulates protein kinase C activityand the expression of γ and ϵ protein kinase C isozymes in therat brain. J Neurochem. 1999;72380- 387
PubMed
Dwivedi  YPandey  GN Quantitation of 5HT2A receptor mRNA in human postmortem brain usingcompetitive RT-PCR. Neuroreport. 1998;93761- 3765
PubMed
Manji  HKMoore  GJChen  G Clinical and preclinical evidence for the neurotrophic effects of moodstabilizers: implications for the pathophysiology and treatment of manic-depressiveillness. Biol Psychiatry. 2000;48740- 754
PubMed
Young  LTWang  JFWoods  CMRobb  JC Platelet protein kinase C α levels in drug-free and lithium-treatedsubjects with bipolar disorder. Neuropsychobiology. 1999;4063- 66
PubMed
Coull  MALowther  SKatona  CLEHorton  RW Altered brain protein kinase C in depression: a postmortem study. Eur Neuropsychopharmacol. 2000;10283- 288
PubMed
Dean  BOpeskin  KPavey  GHill  CKeks  N Changes in protein kinase C and adenylate cyclase in the temporal lobefrom subjects with schizophrenia. J Neural Transm. 1997;1041371- 1381
PubMed
Manji  HKLenox  RH Protein kinase C signaling in the brain: molecular transduction ofmood stabilization in the treatment of manic depressive illness. Biol Psychiatry. 1999;461328- 1351
PubMed
Lopez  JFPalkovits  MArato  MMansour  AAkil  HWatson  SJ Localization and quantification of pro-opiomelanocortin mRNA and glucocorticoidreceptor mRNA in pituitaries of suicide victims. Neuroendocrinology. 1992;56491- 501
PubMed
Pandey  GNDwivedi  Y Effects of adrenal glucocorticoids on protein kinase C (PKC) bindingsites, PKC activity and expression of PKC isozymes in the rat brain. J Neurochem. 2000;74S21D
Banks  GCLi  YReeves  R Differential in vivo modifications of the HMGI(Y) monohistone chromatinproteins modulate nucleosome and DNA interactions. Biochemistry. 2000;398333- 8346
PubMed
Hocevar  BABurns  DJFields  AP Identification of protein kinase C (PKC) phosphorylation sites on humanlamin B: potential role of PKC in nuclear lamina structural dynamics. J Biol Chem. 1993;2687545- 7552
PubMed
Frey  MRClark  JALeontieva  OUronis  JMBlack  ARBack  JD Protein kinase C signaling mediates a program of cell cycle withdrawalin the intestinal epithelium. J Cell Biol. 2000;151763- 778
PubMed
Vertegaal  ACKuiperij  HBYamaoka  SCourtois  Gvan der Eb  MZantema  A Protein kinase C-α is an upstream activator of the IκBkinase complex in the TPA signal transduction pathway to NF-κB in U2OScells. Cell Signal. 2000;12759- 768
PubMed
Yuan  LWGambee  JE Phosphorylation of p300 at serine 89 by protein kinase C. J Biol Chem. 2000;27540946- 40951
PubMed
Nakashima  S Protein kinase Cα (PKCα): regulation and biological function. J Biochem (Tokyo). 2002;132669- 675
PubMed
Leitges  MSchmedt  CGuinamard  RDavoust  JSchaal  SStabel  STarakhovsky  A Immunodeficiency in protein kinase Cβ–deficient mice. Science. 1996;273768- 791
PubMed
Saito  NKikkawa  UNishizuka  YTanaka  C Distribution of protein kinase C–like immunoreactive neuronsin rat brain. J Neurosci. 1988;8369- 382
PubMed
Saito  NShirai  Y Protein kinase Cγ (PKCγ): function of neuron specific isotype. J Biochem (Tokyo). 2002;132683- 687
PubMed
Kano  MHashimoto  KChen  CAbeliovich  AAiba  AKurihara  HWatanabe  MInoue  YTonegawa  S Impaired synapse elimination during cerebellar development in PKCγmutant mice. Cell. 1995;831223- 1231
PubMed
Campbell  JMPayne  APGilmore  DPRussel  DMcGadey  JClarke  DJBranton  RDavies  RWSutcliffe  RG Age change in dopamine levels in the corpus striatum of Albino Swiss(AS) and AS/AGU mutant mice. Neurosci Lett. 1997;23954- 56
PubMed
Payne  APCampbell  JMRussel  DFavor  GSutcliffe  RGBennet  NKDavies  RWStone  TW The AS/AGU rat: a spontaneous model of disruption of degeneration inthe nigrostriatal dopaminergic system. J Anat. 2000;196629- 633
PubMed

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