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

Magali Cazade,Isabelle Bidaud,Philippe Lory,Jean Chemin

doi:10.7554/elife.22331

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 a 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.

Highlights

Voltage-gated Ca2+ channels (VGCCs) are unique among voltage-gated ion channels because the permeant Ca2+ ion acts as an intracellular second messenger, triggering diverse cellular functions (Berridge et al, 2003)
The modulation of VGCC activity plays a pivotal role in the regulation of cardiac and brain activities and this modulation is controlled by a variety of processes, including intracellular Ca2+ itself, which provides an important Ca2+-driven feedback control (Eckert and Chad, 1984; Zuhlke et al, 1999; Peterson et al, 1999; Liang et al, 2003; Green et al, 2007; Tsuruta et al, 2009; Oliveria et al, 2012; Hall et al, 2013; Zamponi et al, 2015)
We found that the Cav3.3 current recorded during an action potential (AP) as well as the ‘rebound’ in the Cav3.3 current associated with the depolarization after potential (DAP) progressively decreased when the protocol was repeated 40 times in cells dialyzed with EGTA (Figure 1a)

Summary

Introduction

Voltage-gated Ca2+ channels (VGCCs) are unique among voltage-gated ion channels because the permeant Ca2+ ion acts as an intracellular second messenger, triggering diverse cellular functions (Berridge et al, 2003). For the Cav1 / L-type VGCCs, this Ca2+ feedback mechanism has been extensively studied in a wide spectrum of biological contexts and a rise in submembrane Ca2+ concentration induces complex effects depending on both the Ca2+ concentration and the duration of the Ca2+ entry (Eckert and Chad, 1984; Zuhlke et al, 1999; Peterson et al, 1999; Liang et al, 2003; Green et al, 2007; Tsuruta et al, 2009; Oliveria et al, 2012; Hall et al, 2013).

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