title: Palmitoylation at two cysteine clusters on the C-terminus of GluN2A and GluN2B differentially control synaptic targeting of NMDA receptors.
abstract: Palmitoylation of NMDARs occurs at two distinct cysteine clusters in the carboxyl-terminus of GluN2A and GluN2B subunits that differentially regulates retention in the Golgi apparatus and surface expression of NMDARs. Mutations of palmitoylatable cysteine residues in the membrane-proximal cluster to non-palmitoylatable serines leads to a reduction in the surface expression of recombinant NMDARs via enhanced internalization of the receptors. Mutations in a cluster of cysteines in the middle of the carboxyl-terminus of GluN2A and GluN2B, leads to an increase in the surface expression of NMDARs via an increase in post-Golgi trafficking. Using a quantitative electrophysiological assay, we investigated whether palmitoylation of GluN2 subunits and the differential regulation of surface expression affect functional synaptic incorporation of NMDARs. We show that a reduction in surface expression due to mutations in the membrane-proximal cluster translates to a reduction in synaptic expression of NMDARs. However, increased surface expression induced by mutations in the cluster of cysteines that regulates post-Golgi trafficking of NMDARs does not increase the synaptic pool of NMDA receptors, indicating that the number of synaptic receptors is tightly regulated.
authors.affiliation: Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Hayley A
authors.initials: HA
authors.lastname: Mattison
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Andres
authors.initials: A
authors.lastname: Barria
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004558:Electric Stimulation; D006056:Golgi Apparatus / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D054878:Lipoylation; D009154:Mutation / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D003545:Cysteine; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor