Ion Trafficking through T-type Ca2+ Channels

Abstract

Voltage-gated Ca2+ channels play a key role in controlling Ca2+ entry during cell depolarization. At least 10 genes encode the main (α1) subunits of voltage-gated Ca2+ channels, which have been grouped into two main classes: the high voltage–activated (HVA) and the low voltage–activated (LVA) channels. HVA channels are primarily involved in muscle contraction, synaptic transmission, and hormone secretion, while LVA channels are associated with action potential generation and repetitive electrical activity. Structurally speaking, the Ca2+ channel α1 subunits forming the pore share strong similarities with other voltage-gated ion channels, in particular with Na+-conducting pores (Hille, 2001). Each α1 subunit has four domains (I–IV) linked together in a single polypeptide chain and each domain contains six putative transmembrane segments (S1–S6), plus a loop (P) that dips partially into the pore to, presumably, form the pore lining. Functionally speaking, the most striking similarity between Ca2+ and Na+ channels is represented by the LVA (T-type) channels, which have comparably low threshold for activation (−50 to −40 mV in 5 mM Ca2+) and inactivate fully and rapidly, if at a 20- to 40-fold lower rate than Na+ channels. Like Na+ channels, fast inactivation of T-type channels is strictly voltage rather than Ca2+ dependent, as in the case of channel types of the HVA family (L, N, P/Q, and R). T-type channels, however, possess other properties that are unique in comparison to other Ca2+ channels: (a) they deactivate more slowly (τdeact = 2.5 ms at −110 mV in 5 mM Ca2+; Carbone and Lux, 1984a); (b) they inactivate at relatively negative holding potentials; (c) they are equally permeable to Ca2+ and Ba2+; (d) they have small single channel conductance; and (e) they outlast membrane-patch excision since they do not require specific metabolic factors to preserve their activity (Carbone and Lux, 1984b, 1987).