Chung Hee Jung, Huang Yan Hua, Lau Lit-Fui, Huganir Richard L
Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2004 Nov 10;24(45):10248-59. doi: 10.1523/JNEUROSCI.0546-04.2004.
Interactions between NMDA receptors (NMDARs) and the PDZ [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] domains of PSD-95/SAP90 (synapse-associated protein with a molecular weight of 90 kDa) family proteins play important roles in the synaptic targeting and signaling of NMDARs. However, little is known about the mechanisms that regulate these PDZ domain-mediated interactions. Here we show that casein kinase II (CK2) phosphorylates the serine residue (Ser1480) within the C-terminal PDZ ligand (IESDV) of the NR2B subunit of NMDAR in vitro and in vivo. Phosphorylation of Ser1480 disrupts the interaction of NR2B with the PDZ domains of PSD-95 and SAP102 and decreases surface NR2B expression in neurons. Interestingly, activity of the NMDAR and Ca2+/calmodulin-dependent protein kinase II regulates CK2 phosphorylation of Ser1480. Furthermore, CK2 colocalizes with NR1 and PSD-95 at synaptic sites. These results indicate that activity-dependent CK2 phosphorylation of the NR2B PDZ ligand regulates the interaction of NMDAR with PSD-95/SAP90 family proteins as well as surface NMDAR expression and may be a critical mechanism for modulating excitatory synaptic function and plasticity.
N-甲基-D-天冬氨酸受体（NMDARs）与突触后致密蛋白95/突触相关蛋白90（分子量90 kDa）（PSD-95/SAP90）家族蛋白的PDZ[突触后致密蛋白95（PSD-95）/盘状大蛋白/紧密连接蛋白1]结构域之间的相互作用，在NMDARs的突触靶向和信号传导中发挥重要作用。然而，对于调节这些PDZ结构域介导的相互作用的机制知之甚少。在此我们表明，酪蛋白激酶II（CK2）在体外和体内使NMDAR的NR2B亚基C末端PDZ配体（IESDV）中的丝氨酸残基（Ser1480）磷酸化。Ser1480的磷酸化破坏了NR2B与PSD-95和SAP102的PDZ结构域的相互作用，并降低了神经元表面NR2B的表达。有趣的是，NMDAR的活性以及Ca2+/钙调蛋白依赖性蛋白激酶II调节Ser1480的CK2磷酸化。此外，CK2与NR1和PSD-95在突触部位共定位。这些结果表明，活性依赖的CK2对NR2B PDZ配体的磷酸化调节了NMDAR与PSD-95/SAP90家族蛋白的相互作用以及表面NMDAR的表达，并且可能是调节兴奋性突触功能和可塑性的关键机制。
