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J. Neurosci. 27 (46): 12577-12583

Copyright © 2007 by the Society for Neuroscience.


Cellular/Molecular

Molecular Mechanisms of Subtype-Specific Inhibition of Neuronal T-Type Calcium Channels by Ascorbate

Michael T. Nelson,1,4 Pavle M. Joksovic,1 Peihan Su,1,4 Ho-Won Kang,6,7 Amy Van Deusen,2 Joel P. Baumgart,2,4 Laurence S. David,5 Terrance P. Snutch,5 Paula Q. Barrett,2 Jung-Ha Lee,6,7 Charles F. Zorumski,8 Edward Perez-Reyes,2,4 , and Slobodan M. Todorovic1,3,4

Departments of 1Anesthesiology, 2Pharmacology, 3Neuroscience, and 4Neuroscience Graduate Program, University of Virginia Health System, Charlottesville, Virginia 22908, 5Michael Smith Laboratories, University of British Columbia, Vancouver British Columbia, Canada V6T 1Z4, 6Department of Life Science and 7Interdisciplinary Program of Biotechnology, Sogang University, Shinsu-Dong, Seoul 121-742, Korea, and 8Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63130

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Box 800710, Charlottesville, VA 22908. Email: st9d{at}virginia.edu

Abstract: T-type Ca2+ channels (T-channels) are involved in the control of neuronal excitability and their gating can be modulated by a variety of redox agents. Ascorbate is an endogenous redox agent that can function as both an anti- and pro-oxidant. Here, we show that ascorbate selectively inhibits native Cav3.2 T-channels in peripheral and central neurons, as well as recombinant Cav3.2 channels heterologously expressed in human embryonic kidney 293 cells, by initiating the metal-catalyzed oxidation of a specific, metal-binding histidine residue in domain 1 of the channel. Our biophysical experiments indicate that ascorbate reduces the availability of Cav3.2 channels over a wide range of membrane potentials, and inhibits Cav3.2-dependent low-threshold-Ca2+ spikes as well as burst-firing in reticular thalamic neurons at physiologically relevant concentrations. This study represents the first mechanistic demonstration of ion channel modulation by ascorbate, and suggests that ascorbate may function as an endogenous modulator of neuronal excitability.

Key Words: ascorbic • calcium current • dorsal root ganglion • DRG • low-threshold calcium channel • oxidation • thalamus


Received for publication May 14, 2007. Revision received Oct. 1, 2007. Accepted for publication Oct. 4, 2007.

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Box 800710, Charlottesville, VA 22908. Email: st9d{at}virginia.edu


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