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
Por:
Vitko I., Bidaud I., Arias J.M., Mezghrani A., Lory P., Perez-Reyes E.
Publicada:
1 ene 2007
Categoría:
Neuroscience (miscellaneous)
Resumen:
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 Cav3.2) 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 Cav3.2 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 Cav3.2 channel overactivity and consequently to absence epilepsy and establish the I-II loop as an important regulator of Cav3.2 channel function and expression. Copyright © 2007 Society for Neuroscience.
Filiaciones:
Department of Pharmacology, University of Virginia, Charlottesville, VA 22904, United States
Departement de Physiologie, Institut de Génomique Fonctionnelle, Université Montpellier I et II, 34090 Montpellier, France
Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 3J5, Canada
Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier Cedex 05, France
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States
All Open Access, Bronze
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