Discs-large (DLG) is clustered by presynaptic innervation and regulates postsynaptic glutamate receptor subunit composition in Drosophila

There are thought to be two classes of glutamate receptors in the Drosophila NMJ: 1) receptors that contain the subunit GluRIIA, and 2) receptors that contain the subunit GluRIIB. In DLG mutants, antibody staining for the glutamate receptor subunit GluRIIA is normal, but antibody staining for the glutamate receptor subunit GluRIIB is significantly reduced. Electrophysiological analysis shows an overall loss of functional postsynaptic glutamate receptors, along with changes in receptor biophysical properties that are consistent with a selective loss of GluRIIB from the synapse. In uninnervated postsynaptic muscles, neither glutamate receptors nor DLG cluster at synapses. DLG clusters normally in the complete absence of glutamate receptors.Our results suggest that DLG controls glutamate receptor subunit composition by selectively stabilizing GluRIIB-containing receptors at the synapse. We also show that DLG, like glutamate receptors, is localized only after the presynaptic neuron contacts the postsynaptic cell. We hypothesize that glutamate receptors and DLG cluster in response to parallel signals from the presynaptic neuron, after which DLG regulates subunit composition by stabilizing (probably indirectly) receptors that contain the GluRIIB subunit. The mechanism(s) stabilizing GluRIIA-containing receptors remains unknown.The molecular mechanisms that target postsynaptic glutamate receptors to the postsynaptic membrane, and keep receptors clustered there, remain unknown. Membrane-associated guanylate kinase proteins (MAGUKs) are cell-cell junction proteins with multiple protein-interaction domains (PDZ, SH3, 4.1/Hook, and a catalytically inactive guanylate kinase/GUK domain) [1-3]. Synaptic MAGUKs are widely believed to be required for recruitment and/or stabilization of a variety of synaptic proteins, including glutamate receptors in the postsynaptic density (PSD) [2,4-6]. Although genetic evidence for MAGUK-dependent clustering of NMDA receptors is strongest, and c