Cloning and characterization of α1H from human heart, a member of the T-type Ca²⁺ channel gene family

Voltage-activated Ca²⁺ channels exist as multigene families that share common structural features. Different Ca²⁺ channels are distinguished by their electrophysiology and pharmacology and can be classified as either low or high voltage-activated channels. Six α1 subunit genes cloned previously code for high voltage-activated Ca²⁺ channels; therefore, we have used a database search strategy to identify new Ca²⁺ channel genes, possibly including low voltage-activated (T-type) channels. A novel expressed sequence-tagged cDNA clone of α1G was used to screen a cDNA library, and in the present study, we report the cloning of α1H (or Ca(v)T.2), a low voltage-activated Ca²⁺ channel from human heart. Northern blots of human mRNA detected more α1H expression in peripheral tissues, such as kidney and heart, than in brain. We mapped the gene, CACNA1H, to human chromosome 16p13.3 and mouse chromosome 17. Expression of α1H in HEK-293 cells resulted in Ca²⁺ channel currents displaying voltage dependence, kinetics, and unitary conductance characteristic of native T-type Ca²⁺ channels. The α1H channel is sensitive to mibefradil, a nondihydropyridine Ca²⁺ channel blocker, with an IC₅₀ of 1.4 μmol/L, consistent with the reported potency of mibefradil for T-type Ca²⁺ channels. Together with α1G, a rat brain T- type Ca²⁺ channel also cloned in our laboratory, these genes define a unique family of Ca²⁺ channels.