Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function

• Published in: The Journal of neuroscience 2011-08, Vol.31 (35), p.12554-12565
• Main Authors: Kiraly, Drew D, Lemtiri-Chlieh, Fouad, Levine, Eric S, Mains, Richard E, Eipper, Betty A
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Avoidance Learning - drug effects; Cerebral Cortex - cytology; Disks Large Homolog 4 Protein; Electric Stimulation - methods; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - genetics; Excitatory Postsynaptic Potentials - physiology; Green Fluorescent Proteins - genetics; Guanine Nucleotide Exchange Factors - deficiency; Guanine Nucleotide Exchange Factors - metabolism; Guanylate Kinases - metabolism; Immunoprecipitation - methods; In Vitro Techniques; Locomotion - drug effects; Locomotion - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroglia - drug effects; Neuroglia - metabolism; Patch-Clamp Techniques - methods; Phenols - pharmacology; Piperidines - pharmacology; Protein Binding - genetics; Pyramidal Cells - physiology; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - physiology; Synaptosomes - drug effects; Synaptosomes - metabolism; Transfection - methods
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.3143-11.2011

The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7(KO)) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7(KO) mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7(KO) animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7(KO) mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.