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2013; Wiley; Volume: 125; Issue: s1 Linguagem: Inglês

10.1111/jnc.12183

1471-4159

Roberto Paes‐de‐Carvalho, Felicidade Santiago, Renato Socodato, Camila C. Portugal, T Encarnac, Ibhadon AO, M Domith, Ana Lúcia Marques Ventura, Isis M. Ornelas, Thais Martins, Erick Correia Loiola, Maria de Lourdes Aguiar Oliveira, F Jacques, Ricardo Bastos, Rosalina Vázquez Tapia, Phil Beart, Mike Robinson, Jéferson Réus da Silva Schulz, Monica J. Carson, Glenn Dallérac, Fabrice Turpin, Gwénola Levasseur, Silvia Sacchi, Pascal Fossat, Jean‐Michel Rivet, Stéphane H. R. Oliet, Loredano Pollegioni, Joseph T. Coyle, Solomon H. Snyder, Mark J. Millan, Jean‐Pierre Mothet,

Neuroscience, Education and Cognitive Function

The avian retina is an excellent model for CNS neurochemical studies and most neurotransmitter systems are present and functional within this tissue.Dopamine and adenosine-dependent adenylyl cyclase systems were previously described in the developing chick retina and also in cultured retinal cells.The major neurotransmitter glutamate is also present in the retina, including NMDA receptors.Since dopamine and NMDA signaling regulate motor behavior and cognition, as well as dopaminergic dysfunction and NMDA hypofunction are both correlated with the development of schizophrenia-like symptoms, we aimed to study the signaling pathways possibly involved in the interaction between these two neurotransmitter systems.Here we present evidence that dopamine modulates NMDA receptor activity through a cyclic AMP/PKA-dependent inhibition of Src kinase activity.Src kinase is a member of kinase family ubiquitously expressed throughout the brain and retina.Src kinase endogenous activation depends on the activity of CSK (a kinase known as the endogenous Src repressor).We investigated how dopamine regulates Src activation and its consequence on NMDA receptor functioning.We show that dopamine D1 receptors depress Src activity through a cAMP/PKA-dependent mechanism.Moreover, D1-mediated PKA activation increases CSK phosphorylation and consequently inhibits Src kinase function.Furthermore, CSK and Src loss-of-function experiments demonstrated that NR2B subunit phosphorylation is decreased by D1 receptor activation in a CSK/Src-dependent fashion.These data show the existence of a novel signaling pathway in which dopamine-mediated Src inhibition promotes NMDA receptor hypofunction in nerve cells.