Abstract
Prenatal cocaine exposure causes sustained phosphorylation of the synaptic anchoring protein, glutamate receptor interacting protein (GRIP1/2), preventing synaptic targeting of the GluR2/3-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs; J. Neurosci. 29: 6308–6319, 2009). Because overexpression of GRIP-associated neuronal rasGEF protein (GRASP-1) specifically reduces the synaptic targeting of AMPARs, we hypothesized that prenatal cocaine exposure enhances GRASP-1 synaptic membrane localization leading to hyper-activation of ras family proteins and heightened actin polymerization. Our results show a markedly increased GRIP1-associated GRASP-1 content with approximately 40% reduction in its rasGEF activity in frontal cortices (FCX) of 21-day-old (P21) prenatal cocaine-exposed rats. This cocaine effect is the result of a persistent protein kinase C (PKC)- and downstream Src tyrosine kinase-mediated GRIP phosphorylation. The hyperactivated PKC also increased membrane-associated GRASP-1 and activated small G-proteins RhoA, cdc42/Rac1 and Rap1 as well as filamentous actin (F-actin) levels without an effect on the phosphorylation state of actin. Since increased F-actin facilitates protein transport, our results suggest that increased GRASP-1 synaptic localization in prenatal cocaine-exposed brains is an adaptive response to restoring the synaptic expression of AMPA-GluR2/3. Our earlier data demonstrated that persistent PKC-mediated GRIP phosphorylation reduces GluR2/3 synaptic targeting in prenatal cocaine-exposed brains, we now show that the increased GRIP-associated GRASP-1 may contribute to the reduction in GluR2/3 synaptic expression and AMPAR signaling defects.
Highlights
Prenatal cocaine exposure results in long-lasting changes in synaptic plasticity that may be responsible for the cognitive deficits in humans and animal models [1], [2], [3]
We demonstrated that reduced GluR2, GluR3-containing amino-3-hydroxy-5-methyl-4isoxazolepropionic acid-type glutamate receptors (AMPARs) on the synaptic membrane is the result of a deficient interaction between AMPARs and synaptic anchoring protein GRIP resulting from sustained protein kinase C (PKC)-mediated GRIP phosphorylation [6]
The GRIP binding partner GRASP-1 can regulate AMPAR targeting by forming a complex with GluR2/3-AMPARs via its association with GRIP [7]
Summary
Prenatal cocaine exposure results in long-lasting changes in synaptic plasticity that may be responsible for the cognitive deficits in humans and animal models [1], [2], [3]. Synaptic plasticity, such as long-term potentiation (LTP) and depression (LTD) are regulated in part by AMPARs [4], [5]. Through its RasGEF domain in the N terminal region, GRASP-1 associates with GRIP1 by binding to the seventh PDZ domain of GRIP located at the C terminal region that is distinct from the GluR2/3 binding site on GRIP [7]. The level of GRIP associated AMPAR(s) is reduced when GRASP-1 is overexpressed [7]
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