HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 2, 1507-1517, January 12, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/2/1507    most recent M607291200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, H. Articles by Zhuo, M. Search for Related Content PubMed PubMed Citation Articles by Wang, H. Articles by Zhuo, M. Social Bookmarking                      What's this?

Genetic Evidence for Adenylyl Cyclase 1 as a Target for Preventing Neuronal Excitotoxicity Mediated by N-Methyl-D-aspartate Receptors^*

Hansen Wang, Bo Gong, Kunjumon I. Vadakkan, Hiroki Toyoda, Bong-Kiun Kaang, and Min Zhuo¹

From the Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada and the Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea

The excessive activation of N-methyl-D-aspartate (NMDA) receptors by glutamate results in neuronal excitotoxicity. cAMP is a key second messenger and contributes to NMDA receptor-dependent synaptic plasticity. Adenylyl cyclases 1 (AC1) and 8 (AC8) are the two major calcium-stimulated ACs in the central nervous system. Previous studies demonstrate AC1 and AC8 play important roles in synaptic plasticity, memory, and persistent pain. However, little is known about the possible roles of these two ACs in glutamate-induced neuronal excitotoxicity. Here, we report that genetic deletion of AC1 significantly attenuated neuronal death induced by glutamate in primary cultures of cortical neurons, whereas AC8 deletion did not produce a significant effect. AC1, but not AC8, contributes to intracellular cAMP production following NMDA receptor activation by glutamate in cultured cortical neurons. AC1 is involved in the dynamic modulation of cAMP-response element-binding protein activity in neuronal excitotoxicity. To explore the possible roles of AC1 in cell death in vivo, we studied neuronal excitotoxicity induced by an intracortical injection of NMDA. Cortical lesions induced by NMDA were significantly reduced in AC1 but not in AC8 knock-out mice. Our findings provide direct evidence that AC1 plays an important role in neuronal excitotoxicity and may serve as a therapeutic target for preventing excitotoxicity in stroke and neurodegenerative diseases.

Received for publication, August 1, 2006 , and in revised form, November 9, 2006.

^* This work was supported by NINDS, National Institutes of Health Grant NS42722, the Canadian Institutes of Health Research (CIHR), the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, and the Canada Research Chair (to M. Z.). 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.

¹ To whom correspondence should be addressed: Dept. of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Bldg., Rm. 3342, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-4018; Fax: 416-978-4940; E-mail: min.zhuo{at}utoronto.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. Wang, H. Fukushima, S. Kida, and M. Zhuo Ca2+/Calmodulin-dependent Protein Kinase IV Links Group I Metabotropic Glutamate Receptors to Fragile X Mental Retardation Protein in Cingulate Cortex J. Biol. Chem., July 10, 2009; 284(28): 18953 - 18962. [Abstract] [Full Text] [PDF]

				N. Masada, A. Ciruela, D. A. MacDougall, and D. M. F. Cooper Distinct Mechanisms of Regulation by Ca2+/Calmodulin of Type 1 and 8 Adenylyl Cyclases Support Their Different Physiological Roles J. Biol. Chem., February 13, 2009; 284(7): 4451 - 4463. [Abstract] [Full Text] [PDF]

				H. Xu, L.-J. Wu, H. Wang, X. Zhang, K. I. Vadakkan, S. S. Kim, H. W. Steenland, and M. Zhuo Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex J. Neurosci., July 16, 2008; 28(29): 7445 - 7453. [Abstract] [Full Text] [PDF]

				H. Wang, L.-J. Wu, F. Zhang, and M. Zhuo Roles of Calcium-Stimulated Adenylyl Cyclase and Calmodulin-Dependent Protein Kinase IV in the Regulation of FMRP by Group I Metabotropic Glutamate Receptors J. Neurosci., April 23, 2008; 28(17): 4385 - 4397. [Abstract] [Full Text] [PDF]

				J. A. Chester and V. J. Watts Adenylyl Cyclase 5: A New Clue in the Search for the "Fountain of Youth"? Sci. Signal., November 20, 2007; 2007(413): pe64 - pe64. [Abstract] [Full Text] [PDF]

				V. J. Watts Adenylyl Cyclase Isoforms as Novel Therapeutic Targets: An Exciting Example of Excitotoxicity Neuroprotection Mol. Interv., April 1, 2007; 7(2): 70 - 73. [Abstract] [Full Text] [PDF]