Pharmacological properties of Ca(v)3.2, a low voltage-activated Ca2+ channel cloned from human heart

Three genes encoding T-type Ca2+ channels have been described but their cor respondence to the various native T-type Ca2+ currents remains uncertain, i n particular, Ca(v)3.2 (or alpha(1H)) was cloned from a human heart library . its message was found abundantly in cardiac tissue, and expressed Ca(v)3. 2 was shown to conduct low voltage-activated currents, which inactivate rap idly and are sensitive to Ni2+ and mibefradil. These observations suggested that Ca(v)3.2 might encode native cardiac T-type Ca2+ channels but more in formation on the pharmacology of Ca(v)3.2 uas needed to confirm this hypoth esis. In the present study, we compare the pharmacology of Ca(v)3.2 express ed in HEK293 cells and of native T-type Ca2+ channels in guinea pig atrial myocytes ("native-T"). (1) Ca(v)3.2 and native-T are insensitive to TTX and to toxins selective for N-, P-. or Q-type Ca2+ channels (omega-CTx-GVIA, o mega-Aga IVA. omega-CTx-MVIIC). (2) The half-maximal blocking concentration (IC50) of mibefradil on Ca(v)3.2 is near that on native-T and the block is similarly voltage-dependent. (3)Ca(v)3.2 is five- to sixfold less sensitiv e than native-T to the 1.4-dihydropyridine (DHP) amlodipine, suggesting a d ifference in the DHP binding site. (4) Both channels display similar (but n ot identical) sensitivities to the inorganic blockers Ni2+ and Cd2+ and the IC(50)s are in the range of values found fur T-type Ca2+ currents in other cell types (5) Ni2+ shifts the voltage dependence of Ca(v)3.2 activation b ut not that of native-T. The many similarities between the two channels sup port the contention that Ca(v)3,2 encodes cardiac T-type Ca2+ channels. The slight differences may be due to species variations and/or to the choice o f splice variant.