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The Journal of Neuroscience, November 14, 2007, 27(46):12577-12583; doi:10.1523/JNEUROSCI.2206-07.2007

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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. Todorovic^1,3,4

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

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 Ca_v3.2 T-channels in peripheral and central neurons, as well as recombinant Ca_v3.2 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 Ca_v3.2 channels over a wide range of membrane potentials, and inhibits Ca_v3.2-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

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Received May 14, 2007; revised Oct. 1, 2007; accepted 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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