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The Journal of Neuroscience, January 10, 2007, 27(2):322-330; doi:10.1523/JNEUROSCI.1817-06.2007

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Neurobiology of Disease
The I–II Loop Controls Plasma Membrane Expression and Gating of Ca_v3.2 T-Type Ca²⁺ Channels: A Paradigm for Childhood Absence Epilepsy Mutations

Iuliia Vitko,^1 * Isabelle Bidaud,^2 * Juan Manuel Arias,¹  Alexandre Mezghrani,² Philippe Lory,² and Edward Perez-Reyes¹

¹Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22904, and ²Departement de Physiologie, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut National de la Santé et de la Recherche Médicale, Unité 661, Université Montpellier I et II, 34090 Montpellier, France

Correspondence should be addressed to either of the following: Philippe Lory, Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier Cedex 05, France, Email: philippe.lory{at}igf.cnrs.fr; or Edward Perez-Reyes, Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Email: eperez{at}virginia.edu

Calcium currents via low-voltage-activated T-type channels mediate burst firing, particularly in thalamic neurons. Considerable evidence supports the hypothesis that overactive T-channels may contribute to thalamocortical dysrhythmia, including absence epilepsy. Single nucleotide polymorphisms in one of the T-channel genes (CACNA1H, which encodes Ca_v3.2) are associated with childhood absence epilepsy in a Chinese population. Because only a fraction of these polymorphisms are predicted to increase channel activity and neuronal firing, we hypothesized that other channel properties may be affected. Here we describe that all the polymorphisms clustered in the intracellular loop connecting repeats I and II (I–II loop) increase the surface expression of extracellularly tagged Ca_v3.2 channels. The functional domains within the I–II loop were then mapped by deletion analysis. The first 62 amino acids of the loop (post IS6) are involved in regulating the voltage dependence of channel gating and inactivation. Similarly, the last 15 amino acids of the loop (pre IIS1) are involved in channel inactivation. In contrast, the central region of I–II loop regulates surface expression, with no significant effect on channel biophysics. Electrophysiology, luminometry, fluorescence-activated cell sorting measurements, and confocal microscopy studies demonstrate that deletion of this central region leads to enhanced surface expression of channels from intracellular compartments to the plasma membrane. These results provide novel insights into how CACNA1H polymorphisms may contribute to Ca_V3.2 channel overactivity and consequently to absence epilepsy and establish the I–II loop as an important regulator of Ca_V3.2 channel function and expression.

Key words: calcium channels; T-type; epilepsy; single nucleotide polymorphisms; electrophysiology; ion channel gating; luminometry; FACS; confocal microscopy

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Received April 28, 2006; revised Oct. 9, 2006; accepted Dec. 2, 2006.

Correspondence should be addressed to either of the following: Philippe Lory, Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier Cedex 05, France, Email: philippe.lory{at}igf.cnrs.fr; or Edward Perez-Reyes, Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Email: eperez{at}virginia.edu

This article has been cited by other articles:

				A. Mezghrani, A. Monteil, K. Watschinger, M. J. Sinnegger-Brauns, C. Barrere, E. Bourinet, J. Nargeot, J. Striessnig, and P. Lory A Destructive Interaction Mechanism Accounts for Dominant-Negative Effects of Misfolded Mutants of Voltage-Gated Calcium Channels J. Neurosci., April 23, 2008; 28(17): 4501 - 4511. [Abstract] [Full Text] [PDF]

				I. I. Arias-Olguin, I. Vitko, M. Fortuna, J. P. Baumgart, S. Sokolova, I. A. Shumilin, A. Van Deusen, M. Soriano-Garcia, J. C. Gomora, and E. Perez-Reyes Characterization of the Gating Brake in the I-II Loop of Cav3.2 T-type Ca2+ Channels J. Biol. Chem., March 28, 2008; 283(13): 8136 - 8144. [Abstract] [Full Text] [PDF]

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