QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 27, 2005, 25(17):4222-4231; doi:10.1523/JNEUROSCI.4701-04.2005

This Article Full Text Full Text (PDF) Submit an eLetter 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 ISI Web of Science 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 ISI Web of Science (19) Citing Articles via Google Scholar Google Scholar Articles by Avshalumov, M. V. Articles by Rice, M. E. Search for Related Content PubMed PubMed Citation Articles by Avshalumov, M. V. Articles by Rice, M. E.

 Previous Article  |  Next Article 

Cellular/Molecular
Endogenous Hydrogen Peroxide Regulates the Excitability of Midbrain Dopamine Neurons via ATP-Sensitive Potassium Channels

Marat V. Avshalumov,¹ Billy T. Chen,¹ Tibor Koós,² James M. Tepper,² and Margaret E. Rice¹

¹Department of Neurosurgery and Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, and ²Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, New Jersey 07102

ATP-sensitive K⁺ (K_ATP) channels link metabolic state to cell excitability. Here, we examined regulation of K_ATP channels in substantia nigra dopamine neurons by hydrogen peroxide (H₂O₂), which is produced in all cells during aerobic metabolism. Blockade of K_ATP channels by glibenclamide (100 nM) or depletion of intracellular H₂O₂ by including catalase, a peroxidase enzyme, in the patch pipette increased the spontaneous firing rate of all dopamine neurons tested in guinea pig midbrain slices. Using fluorescence imaging with dichlorofluorescein to visualize intracellular H₂O₂, we found that moderate increases in H₂O₂ during partial inhibition of glutathione (GSH) peroxidase by mercaptosuccinate (0.1-0.3 mM) had no effect on dopamine neuron firing rate. However, with greater GSH inhibition (1 mM mercaptosuccinate) or application of exogenous H₂O₂, 50% of recorded cells showed K_ATP channel-dependent hyperpolarization. Responsive cells also hyperpolarized with diazoxide, a selective opener for K_ATP channels containing sulfonylurea receptor SUR1 subunits, but not with cromakalim, a selective opener for SUR2-based channels, indicating that SUR1-based K_ATP channels conveyed enhanced sensitivity to elevated H₂O₂. In contrast, when endogenous H₂O₂ levels were increased after inhibition of catalase, the predominant peroxidase in the substantia nigra, with 3-amino-1,2,4-triazole (1 mM), all dopamine neurons responded with glibenclamide-reversible hyperpolarization. Fluorescence imaging of H₂O₂ indicated that catalase inhibition rapidly amplified intracellular H₂O₂, whereas inhibition of GSH peroxidase, a predominantly glial enzyme, caused a slower, smaller increase, especially in nonresponsive cells. Thus, endogenous H₂O₂ modulates neuronal activity via K_ATP channel opening, thereby enhancing the reciprocal relationship between metabolism and excitability.

Key words: basal ganglia; DCF fluorescence imaging; dopamine; K_ATP channels; Parkinson's disease; peroxide; potassium (K⁺) channels; substantia nigra

---

Received Nov 16, 2004; revised March 16, 2005; accepted March 16, 2005.

This article has been cited by other articles:

				F. S. Jones, J. Jing, A. H. Stonehouse, A. Stevens, and G. M. Edelman Caffeine Stimulates Cytochrome Oxidase Expression and Activity in the Striatum in a Sexually Dimorphic Manner Mol. Pharmacol., September 1, 2008; 74(3): 673 - 684. [Abstract] [Full Text] [PDF]

				M. Giustizieri, M. L. Cucchiaroni, E. Guatteo, G. Bernardi, N. B. Mercuri, and N. Berretta Memantine Inhibits ATP-Dependent K+ Conductances in Dopamine Neurons of the Rat Substantia Nigra Pars Compacta J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 721 - 729. [Abstract] [Full Text] [PDF]

				N. Misaki, X. Mao, Y.-F. Lin, S. Suga, G.-H. Li, Q. Liu, Y. Chang, H. Wang, M. Wakui, and J. Wu Iptakalim, a Vascular ATP-Sensitive Potassium (KATP) Channel Opener, Closes Rat Pancreatic beta-Cell KATP Channels and Increases Insulin Release J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 871 - 878. [Abstract] [Full Text] [PDF]

				O. Kann and R. Kovacs Mitochondria and neuronal activity Am J Physiol Cell Physiol, February 1, 2007; 292(2): C641 - C657. [Abstract] [Full Text] [PDF]

				J. Wu, J. Hu, Y.-P. Chen, T. Takeo, S. Suga, J. DeChon, Q. Liu, K.-C. Yang, P. A. St. John, G. Hu, et al. Iptakalim Modulates ATP-Sensitive K+ Channels in Dopamine Neurons from Rat Substantia Nigra Pars Compacta J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 155 - 164. [Abstract] [Full Text] [PDF]

				V. F. Safiulina, R. Afzalov, L. Khiroug, E. Cherubini, and R. Giniatullin Reactive Oxygen Species Mediate the Potentiating Effects of ATP on GABAergic Synaptic Transmission in the Immature Hippocampus J. Biol. Chem., August 18, 2006; 281(33): 23464 - 23470. [Abstract] [Full Text] [PDF]

				L. Bao, M. V. Avshalumov, and M. E. Rice Partial Mitochondrial Inhibition Causes Striatal Dopamine Release Suppression and Medium Spiny Neuron Depolarization via H2O2 Elevation, Not ATP Depletion J. Neurosci., October 26, 2005; 25(43): 10029 - 10040. [Abstract] [Full Text] [PDF]

				R. Geracitano, A. Tozzi, N. Berretta, F. Florenzano, E. Guatteo, M. T. Viscomi, B. Chiolo, M. Molinari, G. Bernardi, and N. B Mercuri Protective role of hydrogen peroxide in oxygen-deprived dopaminergic neurones of the rat substantia nigra J. Physiol., October 1, 2005; 568(1): 97 - 110. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help