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The Journal of Neuroscience, November 1, 2001, 21(21):8464-8472

Regulation of NMDA Receptor Activity by F-Actin and Myosin Light Chain Kinase

Saobo Lei¹, Elzbieta Czerwinska¹, Waldemar Czerwinski¹, Michael P. Walsh², and John F. MacDonald¹

¹ Canadian Institutes of Health Research Group "The Synapse," Departments of Physiology and Pharmacology, University of Toronto, Toronto M5S 1A8, Canada, and ² Canadian Institutes of Health Research Group in Regulation of Vascular Contractility and The Smooth Muscle Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary T2N 4N1, Canada

The postsynaptic density (PSD) at excitatory dendritic synapses comprises a protein complex of glutamate receptors, scaffolding elements, and signaling enzymes. For example, NMDA receptors (NMDARs) are linked to several proteins in the PSD, such as PSD-95, and are also tethered via binding proteins such as -actinin directly to filamentous actin of the cytoskeleton. Depolymerization of the cytoskeleton modulates the activity of NMDARs, and, in turn, strong activation of NMDARs can trigger depolymerization of actin. Myosin, the motor protein of muscular contraction and nonmuscle motility, is also associated with NMDARs and the PSD. We show here that constitutively active myosin light chain kinase (MLCK) enhances NMDAR-mediated whole-cell and synaptic currents in acutely isolated CA1 pyramidal and cultured hippocampal neurons, whereas inhibitors of MLCK depress these currents. This MLCK-dependent regulation was observed in cell-attached patches but was lost after excision to inside-out patches. Furthermore, the enhancement induced by constitutively active MLCK and the depression of MLCK inhibitors were eliminated after depolymerization of the cytoskeleton. NMDARs and MLCK did not colocalize in clusters on the dendrites of cultured hippocampal neurons, further indicating that the effects of MLCK are mediated indirectly via actomyosin. Our results suggest that MLCK enhances actomyosin contractility to either increase the membrane tension on NMDARs or to alter physical relationships between the actin cytoskeleton and the linker proteins of NMDARs.

Key words: NMDA receptors; myosin light chain kinase; actin; glutamate receptors; cytoskeleton; excitatory synaptic currents

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21218464-09$05.00/0

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