Comparative Analysis of the Mechanisms Underlying Nifedipine-Induced Blockade of Three Subtypes of T-Type Ca~(2+) Channels

摘要

We analyzed the effects of nifedipine on a family of recombinant low-threshold Ca~(2+) channels functionally expressed in Xenopus oocytes and formed by three different subunits (α1G, α1H, and α1I). The α1G and α1I channels demonstrated a low sensitivity to nifedipine even in high concentrations (IC_(50) = 98 and 243 μM, maximum blocking intensity A_(max) = 25 and 47%, respectively). At the same time, the above agent effectively blocked channels formed by the α1H-subunit (IC_(50) = 5 μM and A_(max) = 41%). The nifedipine-caused effects were voltage-dependent, and their changes depended on the initial state of the channel. In the case of α1G-subunits, the blockade was determined mostly by binding of nifedipine with closed channels, whereas in the cases of α1H- and α1I-subunits this resulted from binding of nifedipine with channels in the activated and inactivated states. The obtained data allow us to obtain estimates of the pharmacological properties of the above three subtypes of recombinant channels and, in the future, to compare these characteristics with the properties of low-threshold Ca~(2+) channels in native cells.