TY - JOUR
T1 - Prenatal heroin exposure alters cholinergic receptor stimulated activation of the PKCβII and PKCγ isoforms
AU - Yaniv, Shiri P.
AU - Naor, Zvi
AU - Yanai, Joseph
N1 - Funding Information:
Supported by USPHS grant HD 40820 and by grant from Israeli Anti-Drug Authority.
PY - 2004/5/30
Y1 - 2004/5/30
N2 - Prenatal exposure of mice to heroin (SC injection of 10 mg/kg to the dams on gestational days 9-18) resulted at adulthood in behavioral deficits related to septohippocampal cholinergic innervation accompanied with both presynaptic and postsynaptic cholinergic hyperactivity; including an increase membrane PKC activity, and a desensitization of PKC to cholinergic input which were highly correlated with the behavioral performance and were reversed by cholinergic grafting. Therefore, we studied the receptor induced activation of the behaviorally relevant PKCγ and PKCβII isoforms and the less behaviorally relevant PKCα isoform. Time course studies revealed peak translocation after 40 min incubation with carbachol for PKCγ (110% increase from basal, i.e. no carbachol level, P < 0.01), 30 min for phosphorylated PKCβII (130%, P < 0.05) and 5 min for non-phosphorylated PKCβII (64%, P < 0.05) with no peak for alpha. Prenatal heroin abolished the translocation of PKCγ and PKCβII while PKCα remained unaffected. A decrease occurred in basal phosphorylated membrane (-45%, P < 0.01) and cytosol-associated (-29%, P < 0.01) PKCβII, in membrane-associated non-phosphorylated PKCβII (-32%, P < 0.01) and PKCγ (-25%, P < 0.01) and in cytosolic PKCα (-27%, P < 0.01), while membrane-associated PKCα was slightly increased (11%, P < 0.05). The results suggest that prenatal heroin disrupts cholinergic receptor induced PKC translocation and activation with the underlying mechanism of neuroteratogenicity potentially lying in the PKCγ and PKCβII, while PKCα remains unaffected.
AB - Prenatal exposure of mice to heroin (SC injection of 10 mg/kg to the dams on gestational days 9-18) resulted at adulthood in behavioral deficits related to septohippocampal cholinergic innervation accompanied with both presynaptic and postsynaptic cholinergic hyperactivity; including an increase membrane PKC activity, and a desensitization of PKC to cholinergic input which were highly correlated with the behavioral performance and were reversed by cholinergic grafting. Therefore, we studied the receptor induced activation of the behaviorally relevant PKCγ and PKCβII isoforms and the less behaviorally relevant PKCα isoform. Time course studies revealed peak translocation after 40 min incubation with carbachol for PKCγ (110% increase from basal, i.e. no carbachol level, P < 0.01), 30 min for phosphorylated PKCβII (130%, P < 0.05) and 5 min for non-phosphorylated PKCβII (64%, P < 0.05) with no peak for alpha. Prenatal heroin abolished the translocation of PKCγ and PKCβII while PKCα remained unaffected. A decrease occurred in basal phosphorylated membrane (-45%, P < 0.01) and cytosol-associated (-29%, P < 0.01) PKCβII, in membrane-associated non-phosphorylated PKCβII (-32%, P < 0.01) and PKCγ (-25%, P < 0.01) and in cytosolic PKCα (-27%, P < 0.01), while membrane-associated PKCα was slightly increased (11%, P < 0.05). The results suggest that prenatal heroin disrupts cholinergic receptor induced PKC translocation and activation with the underlying mechanism of neuroteratogenicity potentially lying in the PKCγ and PKCβII, while PKCα remains unaffected.
KW - ACh
KW - DAG
KW - DDT
KW - ECL
KW - G protein coupled receptors
KW - GD
KW - GPCRs
KW - HS/Ibg
KW - LTP
KW - acetylcholine
KW - cPKC
KW - cellular protein kinase C
KW - diacylglycerol
KW - dithiothreitol
KW - enhanced chemiluminescence
KW - gestation day
KW - heterogeneous stock mice
KW - long-term potentiation
KW - mAChR
UR - http://www.scopus.com/inward/record.url?scp=2942532637&partnerID=8YFLogxK
U2 - 10.1016/j.brainresbull.2004.04.006
DO - 10.1016/j.brainresbull.2004.04.006
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AN - SCOPUS:2942532637
SN - 0361-9230
VL - 63
SP - 339
EP - 349
JO - Brain Research Bulletin
JF - Brain Research Bulletin
IS - 4
ER -