CLONING AND CHARACTERIZATION OF ALPHA-1H 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 alpha 1 subunit gen es cloned previously code for high voltage-activated Ca2+ channels; th erefore, we have used a database search strategy to identify new Ca2channel genes, possibly including low voltage-activated (T-type) chann els. A novel expressed sequence-tagged cDNA clone of alpha 1G was used to screen a cDNA library, and in the present study, we report the clo ning of alpha 1H (or CavT.2), a low voltage-activated Ca2+ channel fro m human heart. Northern blots of human mRNA detected more alpha 1H exp ression in peripheral tissues, such as kidney and heart, than in brain . We mapped the gene, CACNA1H, to human chromosome 16p13.3 and mouse c hromosome 17. Expression of alpha 1H in HEK-293 cells resulted in Ca2 channel currents displaying voltage dependence, kinetics, and unitary conductance characteristic of native T-type Ca2+ channels. The alpha 1H channel is sensitive to mibefradil, a nondihydropyridine Ca2+ chann el blocker, with an IC50 of 1.4 mu mol/L, consistent with the reported potency of mibefradil for T-type Ca2+ channels. Together with alpha 1 G, a rat brain T-type Ca2+ channel also cloned in our laboratory, thes e genes define a unique family of Ca2+ channels.