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A dominant sodium influx is mediated by a lysine residue in a novel extracellular loop of T-type Cav3 channels. Here we expressed calcium- and sodium-permeable splice variants which have exons 12b and 12a, respectively, as well as mutated channels containing exons Lys-12a-Ala and Ala-12b-Lys. We demonstrate that the mutant channels render high sodium permeability and calcium selectivity, respectively. Modelling illustrate that the pore lysine is salt-bridged to an aspartate residue immediately C-terminal to the second-domain glutamate of the selectivity-filter. We propose that a calcium ion chelated between the aspartate and the selectivity-filter glutamate is knocked-out by the incoming calcium ion in the process of calcium permeation, but sodium ions are repelled. The aspartate is neutralized by the lysine residue in the sodium-permeant variant, allowing for sodium permeation through the selectivity filter ring of four acidic residues akin to the prokaryotic sodium channels with four glutamates in the selectivity filter.

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