Inorganic ions have been used widely to investigate biophysical properties of high voltage-activated calcium channels (HVA: Ca(v)1 and Ca(v)2 families). In contrast, such information regarding low voltage-activated calcium channels (LVA: Ca(v)3 family) is less documented. We have studied the blocking effect of Cd2+, Co2+ and Ni2+ on T-currents expressed by human Ca(v)3 channels: Ca(v)3.1, Ca(v)3.2, and Ca(v)3.3. With the use of the whole-cell configuration of the patch-clamp technique, we have recorded Ca2+ (2 mM: ) currents from HEK-293 cells stably expressing recombinant T-type channels. Cd2+ and Co2+ block was 2- to 3-fold more potent for Ca(v)3.2 channels (EC50 = 65 and 122 microM, respectively) than for the other two LVA channel family members. Current-voltage relationships indicate that Co2+ and Ni2+ shift the voltage dependence of Ca(v)3.1 and Ca(v)3.3 channels activation to more positive potentials. Interestingly, block of those two Ca(v)3 channels by Co2+ and Ni2+ was drastically increased at extreme negative voltages; in contrast, block due to Cd2+ was significantly decreased. This unblocking effect was slightly voltage-dependent. Tail-current analysis reveals a differential effect of Cd2+ on Ca(v)3.3 channels, which can not close while the pore is occupied with this metal cation. The results suggest that metal cations affect differentially T-type channel activity by a mechanism involving the ionic radii of inorganic ions and structural characteristics of the channels pore.