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

J. Biol. Chem., Vol. 279, Issue 38, 39317-39330, September 17, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/38/39317    most recent M403891200v1 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 Chen, J. Articles by Sidhu, A. Search for Related Content PubMed PubMed Citation Articles by Chen, J. Articles by Sidhu, A. Social Bookmarking                      What's this?

D1 Dopamine Receptor Mediates Dopamine-induced Cytotoxicity via the ERK Signal Cascade^*

Jun Chen, Milan Rusnak, Robert R. Luedtke, and Anita Sidhu¶

From the Department of Pediatrics, Georgetown University, Washington, D. C. 20007 and the Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107

Postsynaptic striatal neurodegeneration occurs through unknown mechanisms, but it is linked to high extracellular levels of synaptic dopamine. Dopamine-mediated cytotoxicity of striatal neurons occurs through two distinct pathways: autoxidation and the D1 dopamine receptor-linked signaling pathway. Here we investigated the mitogen-activated protein kinase (MAPK) signaling pathways activated upon the acute stimulation of D1 dopamine receptors. In SK-N-MC neuroblastoma cells, endogenously expressing D1 dopamine receptors, dopamine caused activation of phosphorylated (p-)ERK1/2 and of the stress-signaling kinases, p-JNK and p-p38 MAPK, in a time- and dose-dependent manner. Selective stimulation of D1 receptors with the agonist SKF R-38393 caused p-ERK1/2, but not p-JNK or p-p38 MAPK activation, in a manner sensitive to the receptor-selective antagonist SCH 23390, protein kinase A inhibition (KT5720), and MEK1/2 inhibition (U0126 or PD98059). Activation of ERK by D1 dopamine receptors resulted in oxidative stress and cytotoxicity. In cells transfected with a catalytically defective mutant of MEK1, the upstream ERK-specific kinase, both dopamine- and SKF R-38393-mediated cytotoxicity was markedly attenuated, confirming the participation of the ERK signaling pathway. Cell fractionation studies showed that only a small amount of p-ERK1/2 was translocated to the nucleus, with the majority retained in the cytoplasm. From coimmunoprecipitation studies, p-ERK was found to form stable heterotrimeric complexes with the D1 dopamine receptor and -arrestin2. In cells transfected with the dominant negative mutant of -arrestin2, the formation of such complexes was substantially inhibited. These data provide novel mechanistic insights into the role of ERK in the cytotoxicity mediated upon activation of the D1 dopamine receptor.

Received for publication, April 7, 2004 , and in revised form, May 21, 2004.

^* This work was supported by National Institutes of Health Grant NS-34914. 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.

^¶ To whom correspondence should be addressed: Laboratory of Molecular Neurochemistry, Research Bldg., Rm. W222, 3970 Reservoir Rd. NW, Washington, D. C. 20007. Tel.: 202-687-0282; Fax: 202-687-0279; E-mail: sidhua{at}georgetown.edu.

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

This article has been cited by other articles:

				C. Ma, K. A. Bower, G. Chen, X. Shi, Z.-J. Ke, and J. Luo Interaction between ERK and GSK3{beta} Mediates Basic Fibroblast Growth Factor-induced Apoptosis in SK-N-MC Neuroblastoma Cells J. Biol. Chem., April 4, 2008; 283(14): 9248 - 9256. [Abstract] [Full Text] [PDF]

				T. Nagai, K. Takuma, H. Kamei, Y. Ito, N. Nakamichi, D. Ibi, Y. Nakanishi, M. Murai, H. Mizoguchi, T. Nabeshima, et al. Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortex Learn. Mem., March 2, 2007; 14(3): 117 - 125. [Abstract] [Full Text] [PDF]

				S. Ramachandiran, J. M. Hansen, D. P. Jones, J. R. Richardson, and G. W. Miller Divergent Mechanisms of Paraquat, MPP+, and Rotenone Toxicity: Oxidation of Thioredoxin and Caspase-3 Activation Toxicol. Sci., January 1, 2007; 95(1): 163 - 171. [Abstract] [Full Text] [PDF]

				M. N. Helms, X.-J. Chen, S. Ramosevac, D. C. Eaton, and L. Jain Dopamine regulation of amiloride-sensitive sodium channels in lung cells Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L710 - L722. [Abstract] [Full Text] [PDF]

				C. S. Wilcox Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R913 - R935. [Abstract] [Full Text] [PDF]