Nickel has been proposed to be a selective blocker of low-voltage-activated, T-type calcium channels. However, studies on cloned high-voltage-activated Ca2+ channels indicated that some subtypes, such as α1E, are also blocked by low micromolar concentrations of NiCl2. There are considerable differences in the sensitivity to Ni2+ among native T-type currents, leading to the hypothesis that there may be more than one T-type channel. We confirmed part of this hypothesis by cloning three novel Ca2+ channels, α1G, H, and I, whose currents are nearly identical to the biophysical properties of native T-type channels. In this study we examined the nickel block of these cloned T-type channels expressed in both Xenopus oocytes and HEK-293 cells (10 mM Ba2+). Only α1H currents were sensitive to low micromolar concentrations (IC50 = 13 μM). Much higher concentrations were required to half-block α1I (216 μM) and α1G currents (250 μM). Nickel block varied with the test potential, with less block at potentials above −30 mV. Outward currents through the T channels were blocked even less. We show that depolarizations can unblock the channel and that this can occur in the absence of permeating ions. We conclude that Ni2+ is only a selective blocker of α1H currents and that the concentrations required to block α1G and α1I will also affect high-voltage-activated calcium currents.
