Simulations of calcium channel block by trivalent ions: Gd3+ competes with permeant ions for the selectivity filter

Current through L-type calcium channels (CaV1.2 or dihydropyridine receptor) can be blocked by micromolar concentrations of trivalent cations like the lanthanide gadolinium (Gd 3+). These cations seem to affect both ion permeation a nd pore gating. One effect of trivalents is that the whole-cell peak current recorded after a conditioning voltage pulse depends on [Gd3+], a phenomenon called tonic block. Recently, Babich et al. (J. Gen. Physiol. 129 (2007) 461-475) proposed that tonic block is due to ions competing for a binding site when the channel is closed, and when the channel opens, Gd3+ blocks the pore to prevent the conduction of other ions; tonic block is not due to changes in gating properties, but reflects only permeation. Here, we corroborate this view by computing conductance in a model L-type calcium channel. The model not only reproduces the Gd3+ concentration dependence of the current reduction, but also the effect that substantially more Gd3+ is required to produce similar block in the presence of Sr2+ (compared to Ba2+) and even more in the presence of Ca2+. Tonic block is explained in this model by cations binding in the selectivity filter with the charge/space competition mechanism. In this mechanism, selectivity is determined by the combination of ions that most effectively screen the negative glutamates of the protein while finding space in the midst of the closely-packed carboxylate groups of the glutamate residues