A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.
Ca2+ influx through N-methyl-D-aspartate- (NMDA-) type glutamate receptors plays a critical role in synaptic plasticity in the brain. One of the proteins activated by the increase in Ca2+ is CaM kinase II (CaMKII). Here, we report a novel synaptic Ras-GTPase activating protein (p135 SynGAP) that is a major component of the postsynaptic density, a complex of proteins associated with synaptic NMDA receptors. p135 SynGAP is almost exclusively localized at synapses in hippocampal neurons where it binds to and closely colocalizes with the scaffold protein PSD-95 and colocalizes with NMDA receptors. The Ras-GTPase activating activity of p135 SynGAP is inhibited by phosphorylation by CaMKII located in the PSD protein complex. Inhibition of p135 SynGAP by CaMKII will stop inactivation of GTP-bound Ras and thus could result in activation of the mitogen-activated protein (MAP) kinase pathway in hippocampal neurons upon activation of NMDA receptors.
Chen
H J
HJ
Division of Biology, California Institute of Technology, Pasadena 91125, USA.
Rojas-Soto
M
M
Oguni
A
A
Kennedy
M B
MB
D000818:Animals; D001921:Brain / Q000201:enzymology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013569:Synapses / Q000737:chemistry / Q000201:enzymology*; D018631:ras Proteins / Q000378:metabolism*
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C112617:SynGAP protein p135; D018698:Glutamic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; D018631:ras Proteins