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

This Article Full Text (PDF) Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ramsay, R. R. Articles by Singer, T. P. Search for Related Content PubMed PubMed Citation Articles by Ramsay, R. R. Articles by Singer, T. P. Social Bookmarking                      What's this?

J. Biol. Chem., Vol. 261, Issue 17, 7585-7587, 06, 1986

Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria

RR Ramsay and TP Singer

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an impurity in certain batches of illicit heroin substitutes, is known to cause parkinsonian symptoms and degeneration of the nigrostriatal cells in drug abusers and primates. Neurotoxicity depends on oxidation of MPTP by monoamine oxidase in brain cells to the dihydropyridinium form, which is further oxidized to N-methyl-4-phenylpyridinium (MPP+), the 4- electron oxidation product. The latter is widely believed to be the compound responsible for neuronal destruction and the NADH dehydrogenase of the inner membrane has been postulated to be its target. This enzyme is inhibited, however, only at very high concentrations of MPP+, while the steady-state concentration of MPP+ in the nigrostriatal cells of MPTP-treated animals is several orders of magnitude lower. This paradox has now been resolved by the discovery of an energized uptake system for MPP+ in mitochondria which rapidly concentrates MPP+ to very high concentrations in the mitochondria at micromolar external concentrations. The process is dependent on the electrical gradient of the membrane, has a Km of about 5 mM, and is completely blocked by respiratory inhibitors and uncouplers.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. M. Solano, M. J. Casarejos, J. Menendez-Cuervo, J. A. Rodriguez-Navarro, J. Garcia de Yebenes, and M. A. Mena Glial Dysfunction in Parkin Null Mice: Effects of Aging J. Neurosci., January 16, 2008; 28(3): 598 - 611. [Abstract] [Full Text] [PDF]

				B. Sredni, R. Geffen-Aricha, W. Duan, M. Albeck, F. Shalit, H. M. Lander, N. Kinor, O. Sagi, A. Albeck, S. Yosef, et al. Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson's disease models FASEB J, June 1, 2007; 21(8): 1870 - 1883. [Abstract] [Full Text] [PDF]

				A.C. Williams, L.S. Cartwright, and D.B. Ramsden Parkinson's disease: the first common neurological disease due to auto-intoxication? QJM, March 1, 2005; 98(3): 215 - 226. [Abstract] [Full Text] [PDF]

				K. Nakamura, V. P. Bindokas, J. D. Marks, D. A. Wright, D. M. Frim, R. J. Miller, and U. J. Kang The Selective Toxicity of 1-Methyl-4-phenylpyridinium to Dopaminergic Neurons: The Role of Mitochondrial Complex I and Reactive Oxygen Species Revisited Mol. Pharmacol., August 1, 2000; 58(2): 271 - 278. [Abstract] [Full Text]

				R. G. W. Staal, K. A. Hogan, C.-L. Liang, D. C. German, and P. K. Sonsalla In Vitro Studies of Striatal Vesicles Containing the Vesicular Monoamine Transporter (VMAT2): Rat versus Mouse Differences in Sequestration of 1-Methyl-4-phenylpyridinium J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 329 - 335. [Abstract] [Full Text]

				Y. Kitamura, T. Kosaka, J.-I. Kakimura, Y. Matsuoka, Y. Kohno, Y. Nomura, and T. Taniguchi Protective Effects of the Antiparkinsonian Drugs Talipexole and Pramipexole against 1-Methyl-4-phenylpyridinium-Induced Apoptotic Death in Human Neuroblastoma SH-SY5Y Cells Mol. Pharmacol., December 1, 1998; 54(6): 1046 - 1054. [Abstract] [Full Text]

				R. H. Moseley, L. J. Zugger, and R. W. Van Dyke The Neurotoxin 1-Methyl-4-phenylpyridinium Is a Substrate for the Canalicular Organic Cation/H+ Exchanger J. Pharmacol. Exp. Ther., April 1, 1997; 281(1): 34 - 40. [Abstract] [Full Text]

				P. Chan, D. A. Di Monte, J. W. Langston, and A. M. Janson (+)MK-801 Does Not Prevent MPTP-Induced Loss of Nigral Neurons in Mice J. Pharmacol. Exp. Ther., January 1, 1997; 280(1): 439 - 446. [Abstract] [Full Text]