Low threshold T-type calcium channels as targets for novel epilepsy treatments

Abstract

Low voltage-activated T-type calcium channels were originally cloned in the 1990s and much research has since focused on identifying the physiological roles of these channels in health and disease states. T-type calcium channels are expressed widely throughout the brain and peripheral tissues, and thus have been proposed as therapeutic targets for a variety of diseases such as epilepsy, insomnia, pain, cancer and hypertension. This review discusses the literature concerning the role of T-type calcium channels in physiological and pathological processes related to epilepsy. T-type calcium channels have been implicated in pathology of both the genetic and acquired epilepsies and several anti-epileptic drugs (AEDs) in clinical use are known to suppress seizures via inhibition of T-type calcium channels. Despite the fact that more than 15 new AEDs have become clinically available over the past 20 years at least 30% of epilepsy patients still fail to achieve seizure control, and many patients experience unwanted side effects. Furthermore there are no treatments that prevent the development of epilepsy or mitigate the epileptic state once established. Therefore there is an urgent need for the development of new AEDs that are effective in patients with drug resistant epilepsy, are anti-epileptogenic and are better tolerated. We also review the mechanisms of action of the current AEDs with known effects on T-type calcium channels and discuss novel compounds that are being investigated as new treatments for epilepsy.

Keywords: T-type calcium channels; anti-epileptic drugs; epilepsy.

Figure 1

Biophysical properties of T-type calcium channels. (A) Representative current traces generated by high voltage-activated (HVA; left panel, top) and low voltage-activated (LVA ‘T-type’; right panel, top) calcium channels. HVA calcium channels generally require a greater depolarization to activate than T-type calcium channels (−40 mV compared with −60 mV, respectively). Activation in response to depolarization and subsequent inactivation in response to prolonged depolarization is denoted on current traces. (B) Representative T-type calcium current trace demonstrating the deactivation (closing) process that occurs when the cell is repolarized while the T-type channels are activated (and before inactivation occurs). (C) Representative T-type calcium current trace demonstrating the time-dependent process of recovery from inactivation. A prolonged depolarizing pre-pulse is applied to induce inactivation of the T-type calcium channels. The cell is then repolarized to allow the channels to recover from inactivation before a test pulse is applied. The T-type calcium current is smaller in response to the test pulse than to the pre-pulse because the repolarization time is not sufficient to allow full recovery from inactivation in this example. (D) Schematic representation of the thalamocortical system, showing the proposed expression patterns of the three T-type calcium channel subtypes. (E) Representative electroencephalography (EEG) traces showing activity recorded over the primary somatosensory cortex during resting wakefulness (upper panel) and during an absence seizure (lower panel) in the GAERS absence epilepsy model and demonstrating 7–9 Hz spike-wave discharges