Dopamine promotes NMDA receptor hypofunction in the retina through D1 receptor-mediated Csk activation, Src inhibition and decrease of GluN2B phosphorylation

Sci Rep. 2017 Jan 18:7:40912. doi: 10.1038/srep40912.

Abstract

Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D1 receptors (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CSK Tyrosine-Protein Kinase
  • Calcium / metabolism
  • Chick Embryo
  • Chickens
  • Colforsin / pharmacology
  • Dopamine / pharmacology*
  • Microscopy, Fluorescence
  • Mutagenesis, Site-Directed
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Retina / drug effects*
  • Retina / metabolism
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*

Substances

  • NR2B NMDA receptor
  • RNA, Small Interfering
  • Receptors, Dopamine D1
  • Receptors, N-Methyl-D-Aspartate
  • Colforsin
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • Calcium
  • Dopamine