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Regulation of the Neuron-specific Ras GTPase-activating Protein, synGAP, by Ca2+/Calmodulin-dependent Protein Kinase II

Oh, Jeong S. and Manzerra, Pasquale and Kennedy, Mary B. (2004) Regulation of the Neuron-specific Ras GTPase-activating Protein, synGAP, by Ca2+/Calmodulin-dependent Protein Kinase II. Journal of Biological Chemistry, 279 (17). pp. 17980-17988. ISSN 0021-9258.

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synGAP is a neuron-specific Ras GTPase-activating protein found in high concentration in the postsynaptic density fraction from mammalian forebrain. Proteins in the postsynaptic density, including synGAP, are part of a signaling complex attached to the cytoplasmic tail of the N-methyl-D-aspartate-type glutamate receptor. synGAP can be phosphorylated by a second prominent component of the complex, Ca2+/calmodulin-dependent protein kinase II. Here we show that phosphorylation of synGAP by Ca2+/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. These sites together with other minor phosphorylation sites in the carboxyl tail of synGAP control stimulation of GTPase-activating activity. When three of these sites and four other serines in the carboxyl tail are mutated, stimulation of GAP activity after phosphorylation is reduced to 21 ± 5% compared with 70-95% for the wild type protein. We used phosphosite-specific antibodies to show that, as predicted, phosphorylation of serines 765 and 1123 is increased in cultured cortical neurons after exposure of the neurons to the agonist N-methyl-D-aspartate.

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Kennedy, Mary B.0000-0003-1369-0525
Additional Information:Copyright © 2004 by the American Society for Biochemistry and Molecular Biology. Received for publication, December 23, 2003 , and in revised form, February 11, 2004. Originally published In Press as doi:10.1074/jbc.M314109200 on February 17, 2004 We wish to thank Dr. Hong-Jung Chen for some of the synGAP DNA constructs, Alan J. Rosenstein for excellent technical assistance, Dr. A. K. Dunker for help with PONDRs software, and members of the Kennedy laboratory for many helpful discussions. This work was supported by United States Public Health Services Grants NS17660 and NS28710 (to M. B. K.) and by a fellowship from the John Douglas French Foundation for Alzheimer Research (to J. S. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Deposited On:17 Oct 2006
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