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

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.