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Evidence for common structural determinants of activation and inactivation in T-type Ca2+ channels

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Abstract

One of the most distinctive features of T-type Ca2+ channels is their fast inactivation. Recent structure–function studies indicate that the rate of macroscopic inactivation of these channels is influenced by several structural components, including intracellular linkers, transmembrane segments, and pore loops. The macroscopic inactivation of T-type channels is partially coupled to activation. It is therefore possible that changes in the rate of macroscopic inactivation after alteration in the structure of these channels might actually result from changes in activation kinetics. In this study, we use kinetic simulations to illustrate how the alteration of the rate of channel activation may lead to changes in the rate of macroscopic inactivation. By examining data pooled from several structure–function studies we demonstrate that gating modifications induced by alteration in the channel structure unveils a correlation between the time constants of macroscopic inactivation and activation. This analysis underscores the relevance of considering the inactivation–activation coupling when analyzing the structural determinants of T-type channel inactivation. Furthermore, we demonstrate that slow-inactivating mutants, with modifications in the IIIS6 segment and the proximal C terminus, display significant alterations in the voltage dependencies of activation and deactivation with respect to the wild type channel CaV3.1. Our results indicate that common structures, most likely the S6 transmembrane segments, are involved in the conformational changes occurring during both channel activation and inactivation.

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Acknowledgements

We thank Drs. N. Klugbauer and F. Hofmann for the CaV3.1 clone. We are also grateful to Dr. T. Voets and G. Droogmans for their helpful discussions. The technical assistance of A. Janssens and J. Prenen is greatly acknowledged. This work was supported by the Human Frontiers Science Programme (HFSP Research Grant Ref. RGP 32/2004), the Belgian Federal Government, the Flemish Government, and the Onderzoeksraad KU Leuven (GOA 2004/07, F.W.O. G. 0136.00; F.W.O. G.0172.03, Interuniversity Poles of Attraction Program, Prime Ministers Office IUAP Nr.3P4/23, Excellentiefinanciering EF/95/010).

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  1. Laboratorium voor Fysiologie, KU Leuven, Campus Gasthuisberg, Herestraat 49, 3000, LEUVEN, Belgium

    Karel Talavera & Bernd Nilius

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  1. Karel Talavera
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  2. Bernd Nilius
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Correspondence to Karel Talavera.

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Talavera, K., Nilius, B. Evidence for common structural determinants of activation and inactivation in T-type Ca2+ channels. Pflugers Arch - Eur J Physiol 453, 189–201 (2006). https://doi.org/10.1007/s00424-006-0129-7

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  • DOI: https://doi.org/10.1007/s00424-006-0129-7

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