Regulation of cardiac ion channels by signaling complexes: role of modified leucine zipper motifs

Modulation of ion channels by protein phosphorylation is a dynamic process precisely controlled by the opposing actions of protein kinases and phosphoprotein phosphatases. It is well accepted that the targeting and localization of such signaling enzymes to discrete subcellular compartments or substrates is an important regulatory mechanism ensuring specificity of signaling events in response to local stimuli. Compartmentalization of these enzymes is achieved through association with anchoring or adaptor proteins that target them to subcellular organelles or tether them directly to target substrates via protein–protein interactions. Recently, a novel role for modified leucine zipper motifs in targeting kinases and phosphatases via anchoring proteins has been described for three families of cardiac ion channels: ryanodine-sensitive calcium (Ca2+) release channels, voltage-gated Ca2+ channels, and delayed rectifier potassium (K+) channels. This review will summarize the recent advances made on the regulation of cardiac ion channels by these macromolecular signaling complexes in the normal and diseased heart.