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The Journal of Neuroscience, April 1, 2000, 20(7):2504-2511
Regulation of Long-Term Potentiation by H-Ras through NMDA
Receptor Phosphorylation
Toshiya
Manabe3, 4,
Atsu
Aiba1,
Atsushi
Yamada1,
Taeko
Ichise1,
Hiroyuki
Sakagami5,
Hisatake
Kondo5, and
Motoya
Katsuki1, 2
1 Division of DNA Biology and Embryo Engineering,
Center for Experimental Medicine and 2 Core Research for
Evolutional Science and Technology (CREST), The Institute of Medical
Science, University of Tokyo, Tokyo 108-8639, Japan,
3 Department of Neurophysiology, Faculty of Medicine,
University of Tokyo, Tokyo 113-0033, Japan, 4 Department
of Physiology, Kobe University School of Medicine, Kobe 650-0017,
Japan, and 5 Division of Histology, Department of Cell
Biology, Graduate School of Medical Sciences, Tohoku University, Sendai
980-8575, Japan
The proto-oncogene ras plays a critical role in cell
proliferation and differentiation. However, ras genes
are abundantly expressed in the adult CNS, although neuronal
cells normally do not proliferate. Recently, several lines of evidence
implicated the involvement of Ras signaling pathway in synaptic
plasticity. To explore the role of the Ras proteins in the CNS, we
generated knock-out mice lacking the H-ras gene and then
used them to study the roles of Ras in synaptic transmission and
plasticity. An investigation of protein phosphorylation and synaptic
transmission in H-ras null mutant mice has shown that
the NMDA receptor is a final target molecule of the Ras protein pathway
in the CNS. In the H-ras null mutant hippocampus, the
tyrosine phosphorylation of NR2A ( 1) and NR2B (2) subunits of
NMDA receptors is increased, and, correspondingly, NMDA synaptic
responses are selectively enhanced. In addition, long-term
potentiation is markedly enhanced in mutant mice, most likely
because of a selective enhancement of NMDA synaptic responses. Therefore, although Ras proteins have been implicated in cell proliferation and differentiation, the regulation of activity-dependent synaptic plasticity in the adult animals by downregulation of the
phosphorylation of the NMDA receptor may be another major and pivotal
role for H-Ras protein.
Key words:
long-term potentiation; NMDA receptor; H-Ras; tyrosine
phosphorylation; hippocampus; mutant mice
Copyright © 2000 Society for Neuroscience 0270-6474/00/2072504-08$05.00/0
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