Neuropharmacological studies of clustering molecules expressing in the excitatory synapses

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A human homologue to the discs large (dlg) tumor suppresser protein, NE-dlg (neuronal and endocrine-dlg) has been cloned and characterized (K. Makino et al., Oncogene, 14, 2425, 1997). NE-dlg, also named SAP102, interacts with the NMDA receptor 2B (NR2B) to cluster the receptors in the postsynaptic density. We first documented that NE-dlg interacts with calmodulin and PSD-95 in vitro (J. Biol. Chem., 274, 5782, 1999). We also found an interacting protein, p51-Nedasin, in the brain. The P51-Nedasin interferes the association between NE-dlg and NR2B (J. Biol. Chem. 274, 32204, 1999). We next demonstrated in vitro and in situ phosphorylation of NE-dlg by CaM kinase II in the postsynaptic density fractions and in cultured rat hippocampal neurons. An increased phosphorylation of NE-dlg was also observed following hippocampal long-term potentiation. The increased phosphorylation was prevented by treatment with KN93, a CaM kinase inhibitor but not by protein kinase C inhibitors. We assessed the functional relevance of NE-dlg phosphorylation. CaM kinase Il-dependent NE-dlg phosphorylation prevented its binding to NR2B but promoted the accumulation of NR2B and NR1 in the postsynaptic density. As concerning the cytoplasmic localization of NE-dlg, the phosphorylation of NE-dlg by CaM kinase II is possibly involved in the transport of NR2B and/or NR1 into the postsynaptic density. We recently found that CaM kinase II is also involved in transport of dopamine D2 receptors from Golgi apparatus to the plasma membrane in the neurons, in which a scaffold protein like NE-dlg may underlie its transport mechanisms.