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

Abstract

Cav3 T-type channels are low-voltage-gated channels with rapid kinetics that are classified among the calcium-selective Cav1 and Cav2 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 Cav1 and Cav2 channels but also the sodium ion selectivity of Nav1 sodium channels too. Alternative splicing in the extracellular turret of domain II generates highly sodium-permeable channels, which contribute to low-threshold sodium spikes. Cav3 channels are more ubiquitous among multicellular animals and more widespread in tissues than the more brain centric Nav1 sodium channels in invertebrates. Highly sodium-permeant Cav3 channels can functionally replace Nav1 channels in species where they are lacking, such as in Caenorhabditis elegans.

T-type Channels Become Highly Permeable to Sodium Ions Using an Alternative Extracellular Turret Region (S5-P) Outside the Selectivity Filter

“…Ca v 3 T-type channels are members of the 4ϫ6TM (4 heterologous domains of 6 trans-membrane segments) family of voltage-gated ion channels, which includes calcium (Ca v ) and sodium (Na v ) channels and sodium leak conductance channel (NALCN) (1)(2)(3). The four heterologous domains of 4ϫ6TM channels are considered to have evolved from two rounds of duplication of ancestral channels with one domain, such as the voltage-gated potassium channels (4).…”

Cav3 T-Type Channels As Drug Targets For Treating Epilepsy

“…Functional differences among T-type channels are nuanced, but highly tailored for differing roles. Each T-type channels has unique expression profiles in the nervous system, the cardiovascular system and endocrine systems [6]. Further complicating the diversity is that each of the three T-type channels is subject to unique gene splicing [6].…”

“…'Transient' or 'T-type' class of calcium channels are 'rhythm generator' ion channels, supporting the heartbeat and an even more prominent role in setting brain circuit rhythms within the thalamus [6]. T-type channels are at their highest density in the human body within the thalamus intersecting the circuits underlying normal sleep patterns and the abnormal, pathological rhythms during absence epilepsy.…”

“…that are selective for the inflow of positive calcium ions (and some sodium ions [7]) generating excitability across nerve cell membranes. T-type channels are 'first responders' from the resting state with a low voltage threshold for ion gating [6]. They facilitate a rebound burst of excitation due to input from inhibitory synapses, and can also respond quickly to opening after small inputs from excitatory neurons [6].…”

“…T-type channels are 'first responders' from the resting state with a low voltage threshold for ion gating [6]. They facilitate a rebound burst of excitation due to input from inhibitory synapses, and can also respond quickly to opening after small inputs from excitatory neurons [6]. T-type channels are a primary engine for driving the rhythmic, periodic firing pattern between sets of interconnected neurons, sustaining nerve excitability with any input that pulls neurons out of the resting state [3].…”