title: Dopamine promotes NMDA receptor hypofunction in the retina through D1receptor-mediated Csk activation, Src inhibition and decrease of GluN2B phosphorylation.
abstract: Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D1receptors (D1Rs) and the cytosolic protein tyrosine kinase Src can, independently, modulate the behavior of NMDA-type glutamate receptors (NMDARs). Here we studied the interplay between D1Rs, Src and NMDARs in retinal neurons. We reveal that dopamine-mediated D1R stimulation provoked NMDAR hypofunction in retinal neurons by attenuating NMDA-gated currents, by preventing NMDA-elicited calcium mobilization and by decreasing the phosphorylation of NMDAR subunit GluN2B. This dopamine effect was dependent on upregulation of the canonical D1R/adenylyl cyclase/cAMP/PKA pathway, of PKA-induced activation of C-terminal Src kinase (Csk) and of Src inhibition. Accordingly, knocking down Csk or overexpressing a Csk phosphoresistant Src mutant abrogated the dopamine-induced NMDAR hypofunction. Overall, the interplay between dopamine and NMDAR hypofunction, through the D1R/Csk/Src/GluN2B pathway, might impact on light-regulated synaptic activity in retinal neurons.
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: Renato
authors.initials: R
authors.lastname: Socodato
authors.affiliation: Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.
authors.forename: Felipe N
authors.initials: FN
authors.lastname: Santiago
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: Camila C
authors.initials: CC
authors.lastname: Portugal
authors.affiliation: Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.
authors.forename: Ivan
authors.initials: I
authors.lastname: Domith
authors.affiliation: Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.
authors.forename: Thaísa G
authors.initials: TG
authors.lastname: Encarnação
authors.affiliation: Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.
authors.forename: Erick C
authors.initials: EC
authors.lastname: Loiola
authors.affiliation: Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.|Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niterói, Brazil.
authors.forename: Ana L M
authors.initials: AL
authors.lastname: Ventura
authors.affiliation: Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.|Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Niterói, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cossenza
authors.affiliation: Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: João B
authors.initials: JB
authors.lastname: Relvas
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Rio de Janeiro Federal University, Rio de Janeiro, Brazil.
authors.forename: Newton G
authors.initials: NG
authors.lastname: Castro
authors.affiliation: Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.|Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niterói, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Paes-de-Carvalho
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002118:Calcium / Q000378:metabolism; D002642:Chick Embryo; D002645:Chickens; D005576:Colforsin / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C121001:NR2B NMDA receptor; D034741:RNA, Small Interfering; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D005576:Colforsin; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D002118:Calcium; D004298:Dopamine