Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating

Anders Skov Kristensen, Meagan A Jenkins, Tue G Banke, Arne Schousboe, Yuichi Makino, Richard C Johnson, Richard Huganir, Stephen F Traynelis

    160 Citations (Scopus)

    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.
    Original languageEnglish
    JournalNature Neuroscience
    Volume14
    Issue number6
    Pages (from-to)727-735
    ISSN1097-6256
    DOIs
    Publication statusPublished - 1 Jun 2011

    Keywords

    • Former Faculty of Pharmaceutical Sciences

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