RESUMEN
Prenatal cocaine exposure produces sustained neurobehavioral and brain synaptic changes closely resembling those of animals with defective AMPA receptors (AMPARs). We hypothesized that prenatal cocaine exposure attenuates AMPAR signaling by interfering with AMPAR synaptic targeting. AMPAR function is governed by receptor cycling on and off the synaptic membrane through its interaction with glutamate receptor-interacting protein (GRIP), a PDZ domain protein that is regulated by reversible phosphorylation. Our results show that prenatal cocaine exposure markedly reduces AMPAR synaptic targeting and attenuates AMPAR-mediated synaptic long-term depression in the frontal cortex of 21-d-old rats. This cocaine effect is the result of reduced GRIP-AMPAR interaction caused by persistent phosphorylation of GRIP by protein kinase C (PKC) and Src tyrosine kinase. These data support the restoration of AMPAR activation via suppressing excessive PKC-mediated GRIP phosphorylation as a novel therapeutic approach to treat the neurobehavioral consequences of prenatal cocaine.
Asunto(s)
Proteínas Portadoras/metabolismo , Fármacos del Sistema Nervioso Central/toxicidad , Cocaína/toxicidad , Proteínas del Tejido Nervioso/metabolismo , Efectos Tardíos de la Exposición Prenatal , Receptores AMPA/metabolismo , Sinapsis/efectos de los fármacos , Animales , Femenino , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/crecimiento & desarrollo , Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Fosforilación/efectos de los fármacos , Embarazo , Proteína Quinasa C/metabolismo , Ratas , Ratas Sprague-Dawley , Sinapsis/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
We present data that summarize our findings on the role of taurine in the central nervous system and in particular taurine's interaction with the inhibitory and excitatory systems. In taurine-fed mice, the expression level of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, is elevated. Increased expression of GAD was accompanied by increased levels of GABA. We also found in vitro, that taurine regulates neuronal calcium homeostasis and calcium-dependent processes, such as protein kinase C (PKC) activity. This calcium-dependent kinase was regulated by taurine, whereas the activity of protein kinase A (PKA), a cAMP-dependent, calcium-independent kinase, was not affected. Furthermore, as a consequence of calcium regulation, taurine counteracted glutamate-induced mitochondrial damage and cell death.