Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Abstract

T-type Ca 2+channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca 2+influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca 2+entry via T-type channels can directly regulate intracellular Ca 2+concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca 2+channels, and Na+channels, indicating that they are evolutionarily related. Hence, the α 1-subunits of T-type channels are now designated Ca v 3. Although mRNAs for all three Ca v 3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Ca v 3.2 showing the widest expression. The electrophysiological activities of recombinant Ca v 3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba 2+. The Ca v 3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni 2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.