Emerging role of T-type channels in neurodegeneration.

T-type channels are a class of voltage-gated Ca2+ channels that open at voltages close to resting membrane potential and show fast inactivation and slow inactivation kinetics. Because of their gating properties T-type channels take part to burst firing in neurons and their role in pathophysiology has been traditionally linked to disorders of excitability like epilepsy. Conversely, their possible implication in neurodegeneration has been neglected so far. In the present paper we discuss a number of arguments suggesting that, instead, they have an important role in diverse neurodegenerative diseases. First we will report evidence showing that, because of their biophysical properties, T-type channels are expected to be implicated in neurodegeneration considering, for instance, that they can conduct steady inward Ca2+ currents at moderately depolarized membrane potentials. In addition, we will go through some features of T-type channels regulation that make them obvious candidates in neurodegeneration, like their redox sensitivity, modulation by Zn2+ or epigenetic regulation by transcription factors implicated in neurodegenerative diseases like REST or EGR1. Finally, we will review data from literature showing that both the pharmacological modulation, and the genetic ablation of T-type channels modify the progression of neuronal damage in experimental models in vivo and in vitro of diverse neurodegenerative conditions. In particular, we will show that available evidence suggests that neuroprotection can be afforded by suppressing T-type channel activity in epileptogenesis, stroke and, possibly, in brain aging whereas T-type channel inhibition exacerbates neuronal cell damage in experimental models of motor disorders like Parkinson disease and essential tremor.