Hyper-activated protein kinase c mediates the reduced AMPA receptor surface expression in prenatal cocaine exposed brains: The role for diacylglycerol, diacylglycerol kinase, and 3-phosphoinositide-dependent kinases
Item
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Title
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Hyper-activated protein kinase c mediates the reduced AMPA receptor surface expression in prenatal cocaine exposed brains: The role for diacylglycerol, diacylglycerol kinase, and 3-phosphoinositide-dependent kinases
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Identifier
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d_2009_2013:6737fa68dce0:11964
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identifier
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12621
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Creator
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Liu, Jingjing,
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Contributor
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hoau-yan wang | eitan friedman
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Date
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2013
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Language
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English
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Publisher
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City University of New York.
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Subject
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Neurosciences | Molecular biology | Developmental biology
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Abstract
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Prenatal cocaine exposure induced neurobehavioral and synaptic changes are in part mediated by the defected alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamatergic receptor (AMPAR) neurotransmission. This abnormality of AMPAR system is related to reduced AMPA-GluR2/3 synaptic targeting, which is resulting from sustained phosphorylation of glutamate receptor-interacting protein (GRIP) by hyper-activated protein kinase C (PKC) (Bakshi et al., 2009). The underlying molecular mechanism responsible for PKC hyper-activation, however, remains obscure. Blockade of PKCg and PKC/Mz by their specific pseudosubstrate inhibitors restores AMPAR synaptic targeting, demonstrating that PKC is essential in producing AMPAR abnormalities in prenatal cocaine exposed animal brains. The enhanced PKC activation by prenatal cocaine exposure correlates with an elevated 3-phosphoinositide-dependent protein kinase-1 (PDK1) level, and a persistent increase of synaptic membranous diacylglycerol (DAG) level resulting from down-regulated GRIP-associated DAG kinase (DGKgamma and DGK&zgr;) subtypes. Altogether, these data provide the molecular underpinning for persistent PKC activation in prenatal cocaine-exposed brain and suggest that suppression of PKCgamma and PKC/PKM&zgr; can restore GluR2/3 synaptic targeting and AMPAR function. Importantly, the data derived from this study may provide a novel strategy to treat neurobehavioral abnormalities resulting from prenatal cocaine exposure.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
