title: CaMKIIalpha enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism.
abstract: Long-term potentiation or depression of synaptic function often requires Ca2+ influx via NMDA-type glutamate receptors (NMDARs) and changes in the autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) at Thr286. Autophosphorylated CaMKII binds directly to NMDAR subunits, co-localizes with NMDARs in the postsynaptic density, and phosphorylates NR2B subunits at Ser1303. Here, we demonstrate that CaMKIIalpha enhances the extent and/or rate of desensitization of NMDA-induced macroscopic currents in HEK293 cells co-expressing NR2B with either the NR1(011) or NR1(101) splice variants, without significantly changing other current parameters. In contrast, the extent of desensitization of NMDARs containing NR2A in place of NR2B is significantly decreased by co-expression of CaMKIIalpha. Kinases harboring K42R (inactive kinase) or T286A (autophosphorylation-deficient) mutations are defective in enhancing the desensitization of NR1/NR2B channels. In addition, the CaMKII-dependent enhancement of NR1/NR2B channel desensitization is abrogated by intracellular loading with BAPTA. These data suggest a novel mechanism for Ca2+-dependent negative-feedback regulation of NR2B-containing NMDARs in a CaMKII activity- and autophosphorylation-dependent manner that may modulate NMDAR-mediated synaptic plasticity.
authors.affiliation: Department of Molecular Physiology and Biophysics, The Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sessoms-Sikes
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Honse
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
mesh_terms: D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D016296:Mutagenesis; D009473:Neuronal Plasticity / Q000502:physiology*; D010766:Phosphorylation; D012326:RNA Splicing; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium