Ion-dependent Inactivation of Barium Current through L-type Calcium Channels

It is widely believed that Ba(2+) currents carried through L-type Ca(2+) channels inactivate by a voltage- dependent mechanism similar to that described for other voltage-dependent channels. Studying ionic and gating currents of rabbit cardiac Ca(2+) channels expressed in different subunit combinations in tsA201 cells, we found a phase of Ba(2+) current decay with characteristics of ion-dependent inactivation. Upon a long duration (20 s) depolarizing pulse, I(Ba) decayed as the sum of two exponentials. The slow phase (τ ≈ 6 s, 21°C) was parallel to a reduction of gating charge mobile at positive voltages, which was determined in the same cells. The fast phase of current decay (τ ≈ 600 ms), involving about 50% of total decay, was not accompanied by decrease of gating currents. Its amplitude depended on voltage with a characteristic U-shape, reflecting reduction of inactivation at positive voltages. When Na(+) was used as the charge carrier, decay of ionic current followed a single exponential, of rate similar to that of the slow decay of Ba(2+) current. The reduction of Ba(2+) current during a depolarizing pulse was not due to changes in the concentration gradients driving ion movement, because Ba(2+) entry during the pulse did not change the reversal potential for Ba(2+). A simple model of Ca(2+)-dependent inactivation (Shirokov, R., R. Levis, N. Shirokova, and E. Ríos. 1993. J. Gen. Physiol. 102:1005–1030) robustly accounts for fast Ba(2+) current decay assuming the affinity of the inactivation site on the α(1) subunit to be 100 times lower for Ba(2+) than Ca(2+).