Activation and Involvement of p38 Mitogen-activated Protein Kinase in Glutamate-induced Apoptosis in Rat Cerebellar Granule Cells

doi:10.1074/jbc.272.30.18518

Activation and Involvement of p38 Mitogen-activated Protein Kinase in Glutamate-induced Apoptosis in Rat Cerebellar Granule Cells*

From the ^‡Department of Genetics and Molecular Biology, Institute for Virus Research, the ^¶Department of Biophysics, Graduate School of Science, and the Departments of ^§Neurology and ^‖Physiology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan

Abstract

In the mammalian central nervous system glutamate is the major excitatory neurotransmitter and plays a crucial role in plasticity and toxicity of certain neural cells. We found that glutamate stimulated activation of p38 and stress-activated protein kinase (SAPK, also known as c-Jun N-terminal kinase (JNK)), two subgroup members of the mitogen-activated protein kinase superfamily in matured cerebellar granule cells. The p38 activation was largely mediated by N-methyl-d-aspartate receptors. Furthermore, we have revealed a novel signaling pathway, that is, Ca²⁺-mediated activation of p38 in glutamate-treated granule cells. The glutamate concentration effective for inducing apoptosis correlated with that for inducing p38 activation. SB203580, a specific inhibitor for p38, inhibited glutamate-induced apoptosis. Thus p38 might be involved in glutamate-induced apoptosis in cerebellar granule cells.

Footnotes

↵* This work was supported in part by grants-in-aid from the Ministry of Education, Science and Culture of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵** To whom correspondence should be addressed. Tel.: 81-75-751-3992; Fax: 81-75-751-4019; E-mail: ygotoh{at}virus.kyoto-u.ac.jp.
↵1 The abbreviations used are: NMDA,N-methyl-d-aspartate; dl-AP5,dl-2-amino-5-phosphonopentanoic acid; MAPK, mitogen-activated protein kinase; SAPK, stress-activated protein kinase; JNK, c-Jun N-terminal kinase; PAGE, polyacrylamide gel electrophoresis; NMDG, N-methyl-d-glucamine; DMEM, Dulbecco’s modified Eagle’s medium; DAPI, 4,6-diamidino-2-phenylindole; VSCC, voltage-sensitive Ca²⁺channel.
- Received November 19, 1996.
- Revision received April 14, 1997.