Prenatal cocaine exposure increases synaptic localization of a neuronal RasGEF, GRASP-1 via hyperphosphorylation of AMPAR anchoring protein, GRIP.
PLoS One
; 6(9): e25019, 2011.
Article
in En
| MEDLINE
| ID: mdl-21980374
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carrier Proteins
/
Cocaine
/
Maternal Exposure
/
Ras Guanine Nucleotide Exchange Factors
/
Nerve Tissue Proteins
/
Neurons
Limits:
Animals
/
Pregnancy
Language:
En
Journal:
PLoS One
Journal subject:
CIENCIA
/
MEDICINA
Year:
2011
Document type:
Article
Affiliation country: