Dopamine-induced tyrosine phosphorylation of NR2B (Tyr1472) is essential for ERK1/2 activation and processing of novel taste information

Abstract

Understanding the heterosynaptic interaction between glutamatergic and neuromodulatory synapses is highly important for revealing brain function in health and disease. For instance, the interaction between dopamine and glutamate neurotransmission is vital for memory and synaptic plasticity consolidation, and it is known to converge on extracellular signal-regulated kinase (ERK)-MAPK signaling in neurons. Previous studies suggest that dopamine induces N-methyl-D-aspartate (NMDA) receptor phosphorylation at the NR2B Y1472 subunit, influencing receptor internalization at the synaptic plasma membrane. However, it is unclear whether this phosphorylation is upstream to and/or necessary for ERK1/2 activation, which is known to be crucial for synaptic plasticity and memory consolidation. Here, we tested the hypothesis that tyrosine phosphorylation of NR2B at Y1472 is correlated with ERK1/2 activation by dopamine and necessary for it as well. We find that dopamine receptor D1, but not D2, activates ERK1/2 and leads to NR2BY1472 phosphorylation in the mature hippocampus and cortex. Moreover, our results indicate that NR2B Y1472 phosphorylation is necessary for ERK1/2 activation. Importantly, application of dopamine or the D1 receptor agonist SKF38393 to hippocampal slices from NR2B F1472 mutant mice did not result in ERK1/2 activation, suggesting this site is not only correlated with ERK1/2 activation by dopamine stimulation, but also necessary for it. In addition, NR2B F1472 mice show impairment in learning of attenuation of taste neophobia but not associative taste learning. Our study shows that the dopaminergic and glutamatergic transmission converge on the NMDA receptor itself, at the Y1472 site of the NR2B subunit, and that this convergence is essential for ERK1/2 activation in the mature brain and for processing new sensory information in the cortex.

Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction

“…Dopamine-induced cAMP/PKA pathway enhances the electrophysiological effects of ongoing glutamatergic input onto MSN dendritic spines by modulating ion channels within synapses (Surmeier et al, 2007) that increases calcium-dependent ERK activation leading to c-fos promoter activation. One biochemical mechanism involves D1/cAMP/PKA phosphorylation of NMDA receptors in the synapse to enhance activation of the NMDA/calcium/ERK pathway (David et al, 2014; Ron, 2004). Another biochemical mechanism proposes that D1/cAMP/PKA activates a DARPP32-mediated mechanism that indirectly enhances NMDA/calcium activation of the ERK pathway (Valjent et al, 2005).…”

Adenosine A2A receptors are required for glutamate mGluR5‐ and dopamine D1 receptor‐evoked ERK1/2 phosphorylation in rat hippocampus: involvement of NMDA receptor

“…Recent results by David et al . () suggest that the dopamine D1 receptor‐evoked NR2B phosphorylation at Tyr1472 not only correlates well with the D1R‐evoked ERK1/2 activation, but it is also necessary for it.…”

“…Our results further demonstrated that stimulation of dopamine D1 receptors in hippocampal slices also induces a significant increase in both ERK1/2 activation and NR2B(Tyr1472) phosphorylation, confirming the data of David et al . (). Moreover we have shown for the first time that the D1R‐mediated ERK1/2 activation and NR2B(Tyr1472) phosphorylation occur under the permissive control of A 2A receptors.…”

“…; David et al . ), and the (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo [a,d]cyclohepten‐5,10‐imine maleate (MK801) (100 μΜ) (Yang et al . ), the PP1, ZM241385, ADA, AP5, and MK801 were applied 30 min prior to the incubation of slices with the drug combinations.…”

“…In addition, a recent study (David et al . ) showed that activation of D1R induces both the NR2B(Tyr1472) phosphorylation and ERK1/2 activation.…”