Permeation and Selectivity in Calcium Channels

Recent advances—both experimental and theoretical—provide a tentative image of the structures in Ca channels that make them exceptionally selective. The image is very different from K channels, which obtain high selectivity with a rigid pore that tightly fits K⁺ ions and is lined by carbonyl oxygens of the polypeptide backbone. Ca channels rely on four glutamate residues (the EEEE locus), whose carboxyl side chains likely reach into the pore lumen to interact with passing Ca²⁺ ions. The structure is thought to be flexible, tightly binding a single Ca²⁺ ion in order to block Na⁺ flux but rearranging to interact with multiple Ca²⁺ ions to allow Ca²⁺ flux. The four glutamates are not equivalent, a fact that seems important for Ca²⁺ permeation. This review describes the experimental evidence that leads to these conclusions and the attempts by theorists to explain the combination of high selectivity and high flux that characterizes Ca channels.