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

Abstract

Voltage-gated Ca ²⁺ channels are involved in numerous physiological functions and various mechanisms finely tune their activity, including the Ca ²⁺ ion itself. This is well exemplified by the Ca ²⁺-dependent inactivation of L-type Ca ²⁺ channels, whose alteration contributes to the dramatic disease Timothy Syndrome. For T-type Ca ²⁺ channels, a long-held view is that they are not regulated by intracellular Ca ²⁺. Here we challenge this notion by using dedicated electrophysiological protocols on both native and expressed T-type Ca ²⁺ channels. We demonstrate that a rise in submembrane Ca ²⁺ induces a large decrease in T-type current amplitude due to a hyperpolarizing shift in the steady-state inactivation. Activation of most representative Ca ²⁺-permeable ionotropic receptors similarly regulate T-type current properties. Altogether, our data clearly establish that Ca ²⁺ 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 Ca ²⁺ channels to their physiological roles.

DOI: http://dx.doi.org/10.7554/eLife.22331.001

eLife digest

Neurons, muscle cells and many other types of cells use electrical signals to exchange information and coordinate their behavior. Proteins known as calcium channels sit in the membrane that surrounds the cell and can generate electrical signals by allowing calcium ions to cross the membrane and enter the cell during electrical activities. Although calcium ions are needed to generate these electrical signals, and for many other processes in cells, if the levels of calcium ions inside cells become too high they can be harmful and cause disease.

Cells have a “feedback” mechanism that prevents calcium ion levels from becoming too high. This mechanism relies on the calcium ions that are already in the cell being able to close the calcium channels. This feedback mechanism has been extensively studied in two types of calcium channel, but it is not known whether a third group of channels – known as Cav3 channels – are also regulated in this way.

Cav3 channels are important in electrical signaling in neurons and have been linked with epilepsy, chronic pain and various other conditions in humans. Cazade et al. investigated whether calcium ions can regulate the activity of human Cav3 channels. The experiments show that these channels are indeed regulated by calcium ions, but using a distinct mechanism to other types of calcium channels. For the Cav3 channels, calcium ions alter the gating properties of the channels so that they are less easily activated . As a result, fewer Cav3 channels are “available” to provide calcium ions with a route into the cell.

The next steps following on from this work will be to identify the molecular mechanisms underlying this new feedback mechanism. Another challenge will be to find out what role this calcium ion-driven feedback plays in neurological disorders that are linked with altered Cav3 channel activity.

DOI: http://dx.doi.org/10.7554/eLife.22331.002