title: Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating.
abstract: The function, trafficking and synaptic signaling of AMPA receptors are tightly regulated by phosphorylation. Ca(2+)/calmodulin-dependent kinase II (CaMKII) phosphorylates the GluA1 AMPA receptor subunit at Ser831 to increase single-channel conductance. We show that CaMKII increases the conductance of native heteromeric AMPA receptors in mouse hippocampal neurons through phosphorylation of Ser831. In addition, co-expression of transmembrane AMPA receptor regulatory proteins (TARPs) with recombinant receptors is required for phospho-Ser831 to increase conductance of heteromeric GluA1-GluA2 receptors. Finally, phosphorylation of Ser831 increases the efficiency with which each subunit can activate, independent of agonist efficacy, thereby increasing the likelihood that more receptor subunits will be simultaneously activated during gating. This underlies the observation that phospho-Ser831 increases the frequency of openings to larger conductances rather than altering unitary conductance. Together, these findings suggest that CaMKII phosphorylation of GluA1-Ser831 decreases the activation energy for an intrasubunit conformational change that regulates the conductance of the receptor when the channel pore opens.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Anders S
authors.initials: AS
authors.lastname: Kristensen
authors.forename: Meagan A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Tue G
authors.initials: TG
authors.lastname: Banke
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.forename: Richard C
authors.initials: RC
authors.lastname: Johnson
authors.forename: Richard
authors.initials: R
authors.lastname: Huganir
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000166:cytology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D008565:Membrane Proteins; D018091:Receptors, AMPA; D012694:Serine