Analysis of Differential Effects of Pb2+on Protein Kinase C Isozymes

Sun, Xiaoyan; Tian, Xintian; Tomsig, Jose L.; Suszkiw, Janusz B.

doi:10.1006/taap.1999.8622

Cited by 91 publications

(65 citation statements)

References 9 publications

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“…In this regard, it is of interest that a blockade of ␣1-ARs can help to reduce symptoms of PTSD (63), although it is not known if this helps rescue prefrontal cortical gray matter. Finally, an environmental toxin-lead-can mimic Ca 2ϩ , resulting in elevated PKC activity (64)(65)(66). The current results suggest that an increase in PKC signaling may contribute to a loss of prefrontal cortical gray matter in subjects with lead poisoning.…”

Section: Discussionmentioning

confidence: 76%

Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress

Hains

Maciejewski

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

202

186

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The prefrontal cortex r regulates behavior, cognition, and emotion by using working memory. Prefrontal functions are impaired by stress exposure. Acute, stress-induced deficits arise from excessive protein kinase C (PKC) signaling, which diminishes prefrontal neuronal firing. Chronic stress additionally produces architectural changes, reducing dendritic complexity and spine density of cortico-cortical pyramidal neurons, thereby disrupting excitatory working memory networks. In vitro studies have found that sustained PKC activity leads to spine loss from hippocampalcultured neurons, suggesting that PKC may contribute to spine loss during chronic stress exposure. The present study tested whether inhibition of PKC with chelerythrine before daily stress would protect prefrontal spines and working memory. We found that inhibition of PKC rescued working memory impairments and reversed distal apical dendritic spine loss in layer II/III pyramidal neurons of rat prelimbic cortex. Greater spine density predicted better cognitive performance, the first direct correlation between pyramidal cell structure and working memory abilities. These findings suggest that PKC inhibitors may be neuroprotective in disorders with dysregulated PKC signaling such as bipolar disorder, schizophrenia, post-traumatic stress disorder, and lead poisoning-conditions characterized by impoverished prefrontal structural and functional integrity. bipolar disorder ͉ post-traumatic stress disorder ͉ working memory ͉ chelerythrine ͉ lead poisoning

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Section: Discussionmentioning

confidence: 76%

Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress

Hains

Maciejewski

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

202

186

View full text Add to dashboard Cite

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“…At picomolar concentrations Pb 2+ is an effective activator of PKC (Markovac and Goldstein, 1988;Long et al, 1994), but it inhibits the enzyme in the micromolar range and through a mechanism not due to the competition with Ca 2+ (Murakami et al, 1993). These apparently conflicting observations led to a proposed model of Pb 2+ as a partial agonist of PKC, capable of both activating and inhibiting the enzyme (Tomsig and Suszkiw, 1995) and this model was later tested and characterized using recombinant human isozymes (Sun et al, 1999). More than 10 isoforms of the PKC family have been described.…”

Section: Protein Kinase Cmentioning

confidence: 98%

Molecular targets of lead in brain neurotoxicity

Marchetti

2003

neurotox res

151

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The detrimental effects of lead poisoning have been well known since ancient times, but some of the most severe consequences of exposure to this metal have only been described recently. Lead [Pb(II)] affects the higher functions of the central nervous system and undermines brain growth, preventing the correct development of cognitive and behavioral functions. As an established neurotoxin, Pb(II) crosses the blood-brain barrier rapidly and concentrates in the brain. The mechanisms of lead neurotoxicity are complex and still not fully understood, but recent findings recognized that both Ca(II) dependent proteins and neurotransmitters receptors represent significant targets for Pb(II). In particular, acute and chronic exposure to lead would predominantly affect two specific protein complexes: protein kinase C and the N-methyl-D-aspartate subtype of glutamate receptor. These protein complexes are deeply involved in learning and cognitive functions and are also thought to interact significantly with each other to mediate these functions. This review outlines the most recent hypotheses and evidences that link lead poisoning to impairment of these protein functions, as well as the in vitro experimental approaches that are most likely to provide information on basic mechanicistic processes.

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“…PKC activity is altered by lead in a complex fashion, both activating the enzyme and inhibiting it by competitive and noncompetitive actions (49). The various PKC isozymes are affected differentially (50). PKC has at least 11 different isozymes, each with differences in cofactor dependence and response to phospholipid metabolites (51).…”

Section: Lead and Pcbs Have Similar Effects On Ltpmentioning

confidence: 99%

Electrophysiologic and behavioral effects of perinatal and acute exposure of rats to lead and polychlorinated biphenyls.

Carpenter

Hussain

Berger

et al. 2002

Environ Health Perspect

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Lead and polychlorinated biphenyls (PCBs) both cause a reduction of intelligence quotient and behavioral abnormalities in exposed children that have features in common with attention deficit hyperactivity disorder. We have used rats as a model to study the effects of both perinatal and acute exposure to lead or PCBs in an effort to compare and understand the mechanisms of these nervous system decrements. Long-term potentiation (LTP) is an electrophysiologic measurement that correlates well with cognitive ability. We have determined the effects of chronic perinatal exposure to lead or PCB 153 as well as acute application of these substances to isolated brain slices, with recordings in two areas of the hippocampus, CA1 and CA3. Both substances, whether chronically or acutely applied, significantly reduced LTP in CA1 in animals at age 30 and 60 days. In CA3, they reduced LTP in 30-day animals but potentiated it in 60-day animals. Although neither lead nor PCB 153 alters baseline synaptic transmission at low stimulus strengths, at higher levels they induce changes in the same direction as those of LTP. These results show surprisingly similar actions of these quite different chemicals, and the similarity of effects on chronic and acute application indicates that effects are both pharmacologic and developmental. Behavioral studies of rats exposed to PCBs from contaminated fish show hyperactivity, impulsiveness, and increased frustration relative to unexposed controls. These results demonstrate that lead and PCBs have similar effects on synaptic plasticity and behavior and suggest that the compounds may act through a common mechanism. Key words: brain slice, extinction, frustration, hippocampus, hyperactivity, input-output curves, long-term potentiation, perinatal exposure.

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Analysis of Differential Effects of Pb2+on Protein Kinase C Isozymes

Cited by 91 publications

References 9 publications

Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress

Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress

Molecular targets of lead in brain neurotoxicity

Electrophysiologic and behavioral effects of perinatal and acute exposure of rats to lead and polychlorinated biphenyls.

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