Cav3 T-type channels: regulators for gating, membrane expression, and cation selectivity

Ca(v)3 T-type channels are low-voltage-gated channels with rapid kinetics that are classified among the calcium-selective Ca(v)1 and Ca(v)2 type channels. Here, we outline the fundamental and unique regulators of T-type channels. An ubiquitous and proximally located "gating brake" works in concert with the voltage-sensor domain and S6 alpha-helical segment from domain II to set the canonical low-threshold and transient gating features of T-type channels. Gene splicing of optional exon 25c (and/or exon 26) in the short III-IV linker provides a developmental switch between modes of activity, such as activating in response to membrane depolarization, to channels requiring hyperpolarization input before being available to activate. Downstream of the gating brake in the I-II linker is a key region for regulating channel expression where alternative splicing patterns correlate with functional diversity of spike patterns, pacemaking rate (especially in the heart), stage of development, and animal size. A small but persistent window conductance depolarizes cells and boosts excitability at rest. T-type channels possess an ion selectivity that can resemble not only the calcium ion exclusive Ca(v)1 and Ca(v)2 channels but also the sodium ion selectivity of Na(v)1 sodium channels too. Alternative splicing in the extracellular turret of domain II generates highly sodium-permeable channels, which contribute to low-threshold sodium spikes. Ca(v)3 channels are more ubiquitous among multicellular animals and more widespread in tissues than the more brain centric Na(v)1 sodium channels in invertebrates. Highly sodium-permeant Ca(v)3 channels can functionally replace Na(v)1 channels in species where they are lacking, such as in Caenorhabditis elegans.