Low-voltage-activated (T-type) calcium-channel genes identified

Tremendous advances have been made in recent years regarding the molecular biology of voltage-dependent Ca2+ channels[1]. These macromolecules are composed of a pore-forming α1 subunit with four homologous domains (I–IV), each with six transmembrane segments (S1–S6). Accessory subunits, which modify functional expression and gating, include β, α2–δ and γ. Various neuronal α1 subunits have been cloned, although until recently they all seemed to encode channels activated by relatively strong membrane depolarization, the so-called high-voltage-activated Ca2+ channels. In general, members of this functional class, which includes L, N, P/Q and R types, are thought to mediate calcium entry, especially that triggered by action potentials. This leads to increments in intracellular Ca2+ concentration and thus to secondary actions, such as neurotransmitter release or excitation–contraction coupling. The other major class of Ca2+ channels consists of low-voltage-activated (LVA), or T-type (for transient or tiny[2]), channels. These channels can be activated by membrane-potential changes that are subthreshold for action-potential generation. When expressed at high levels in neurons, burst-discharge (see below) and some forms of intrinsic rhythm generation are promoted[3]. A number of other putative T-channel functions in neuronal and non-neuronal cells have been identified[2, 3]. Many attempts have been made to identify the molecular basis of this important Ca2+ channel family, but they have been met with little success. Recently, Perez-Reyes and colleagues described three genes encoding new members of the family of α1 calcium-channel subunits, including α1G (Ref. [4]) and two related genes (α1H and α1I). High levels of mRNA for the α1G subunit are found in the brain, especially in some regions noted for neuronal burst firing, such as the thalamus and amygdala, but also in the cerebellum, where a subpopulation of neurons, the Purkinje cells, demonstrate phenotypical burst firing. When expressed in Xenopus oocytes these channels demonstrate all the properties of the classical T-type current[2, 5]. Thus, α1G can be identified unambiguously as a new member of the LVA or T-channel family.