Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate

Michael T. Nelson, Pavle M. Joksovic, Peihan Su, Ho Won Kang, Amy Van Deusen, Joel P. Baumgart, Laurence S. David, Terrance P. Snutch, Paula Q. Barrett, Jung Ha Lee, Charles F. Zorumski, Edward Perez-Reyes, Slobodan M. Todorovic

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94 Scopus citations

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.

Original languageEnglish
Pages (from-to)12577-12583
Number of pages7
JournalJournal of Neuroscience
Volume27
Issue number46
DOIs
StatePublished - Nov 14 2007

Keywords

  • Ascorbic
  • Calcium current
  • DRG
  • Dorsal root ganglion
  • Low-threshold calcium channel
  • Oxidation
  • Thalamus

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    Nelson, M. T., Joksovic, P. M., Su, P., Kang, H. W., Van Deusen, A., Baumgart, J. P., David, L. S., Snutch, T. P., Barrett, P. Q., Lee, J. H., Zorumski, C. F., Perez-Reyes, E., & Todorovic, S. M. (2007). Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate. Journal of Neuroscience, 27(46), 12577-12583. https://doi.org/10.1523/JNEUROSCI.2206-07.2007