Activity-dependent regulation of T-type calcium channels by submembrane calcium ions

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Abstract

Voltage-gated Ca²⁺ channels are involved in numerous physiological functions and various mechanisms finely tune their activity, including the Ca²⁺ ion itself. This is well exemplified by the Ca²⁺-dependent inactivation of L-type Ca²⁺ channels, whose alteration contributes to the dramatic disease Timothy Syndrome. For T-type Ca²⁺ channels, a long-held view is that they are not regulated by intracellular Ca²⁺. Here we challenge this notion by using dedicated electrophysiological protocols on both native and expressed T-type Ca²⁺ channels. We demonstrate that a rise in submembrane Ca²⁺ induces a large decrease in T-type current amplitude due to an important hyperpolarizing shift in the steady-state inactivation. Activation of most representative Ca²⁺-permeable ionotropic receptors similarly regulate T-type current properties. Altogether, our data clearly establish that Ca²⁺ entry exerts a feedback control on T-type channel activity, by modulating the channel availability, a mechanism that critically links cellular properties of T-type Ca²⁺ channels to their physiological roles.

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Magali Cazade

IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France

Competing interests
The authors declare that no competing interests exist.
Isabelle Bidaud

IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France

Competing interests
The authors declare that no competing interests exist.
Philippe Lory

IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France

For correspondence
philippe.lory@igf.cnrs.fr

Competing interests
The authors declare that no competing interests exist.
Jean Chemin

IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France

For correspondence
jean.chemin@igf.cnrs.fr

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6089-5964

Funding

Agence Nationale de la Recherche (ANR-10-BLAN-1601)

Philippe Lory

Laboratory of excellence in Ion Channel Science and Therapeutics (LabEx ICST)

Philippe Lory

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal use procedures were done in accordance with the directives of the French Ministry of Agriculture (A 34-172-41).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.