title: Simulations of calcium channel block by trivalent cations: Gd(3+) competes with permeant ions for the selectivity filter.
abstract: Current through L-type calcium channels (Ca(V)1.2 or dihydropyridine receptor) can be blocked by micromolar concentrations of trivalent cations like the lanthanide gadolinium (Gd(3+)). It has been proposed that trivalent block is due to ions competing for a binding site in both the open and closed configuration, but possibly with different trivalent affinities. Here, we corroborate this general view of trivalent block by computing conductance of a model L-type calcium channel. The model qualitatively reproduces the Gd(3+) concentration dependence and the effect that substantially more Gd(3+) is required to produce similar block in the presence of Sr(2+) (compared to Ba(2+)) and even more in the presence of Ca(2+). Trivalent block is explained in this model by cations binding in the selectivity filter with the charge/space competition mechanism. This is the same mechanism that in the model channel governs other selectivity properties. Specifically, 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.
authors.affiliation: Department of Physical Chemistry, University of Pannonia, Veszprém, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Malasics
authors.forename: Dezso
authors.initials: D
authors.lastname: Boda
authors.forename: Mónika
authors.initials: M
authors.lastname: Valiskó
authors.forename: Douglas
authors.initials: D
authors.lastname: Henderson
authors.forename: Dirk
authors.initials: D
authors.lastname: Gillespie
mesh_terms: D001464:Barium / Q000737:chemistry; D002118:Calcium / Q000737:chemistry; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D005682:Gadolinium / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D001464:Barium; D005682:Gadolinium; D002118:Calcium