Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca²⁺ signaling in spines

The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca²⁺ permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca²⁺ signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca²⁺permeation and Ca²⁺signaling in spines. Activation of β-adrenergic and D₁/D₅-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDARCa²⁺permeation, synaptic currents, and Ca²⁺ rises in dendritic spines. Wefurther show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca²⁺ signaling at synapses and regulated by the emotional response to stress.