Cytoskeleton regulation of ion channels.

C ardiac arrhythmia is one of the leading causes of sudden death in developed countries, and results from abnormal cardiac electric activity. Regular beat-to-beat cardiac excitability requires the coordinated activity of membrane-bound ionophoric proteins that are channels and transporters. Aberrant currents can result from either changes in the gating properties of ionophores or altered trafficking to their appropriate membrane subdomain. Mutations in the genes of ionophoric proteins result in inherited human arrhythmogenic syndromes. Although the mutations of channel proteins can affect biophysical gating properties, 1 most inherited arrhyth-mia disorders likely result from altered protein trafficking rather than gating. 2–5 In addition, mutations in the proteins that make up the trafficking apparatus, namely the cytoskeletal and associated proteins, can also result in arrhythmia disorders. Ankyrins are an important family of cytoskeleton-related adapter proteins known for localizing proteins to specialized subdomains in a variety of cells types. 1 Ankyrins interact with ionophoric proteins, whereas their central domain binds to members of the β-spectrin family of actin-associated cytoskeleton, thereby linking the channel to the actin cyto-skeleton. Ankyrins in the vertebrate heart are encoded by 3 genes: ankyrin-R (ANK1), ankyrin-B (ANK2), and ankyrin-G (ANK3), with the ankyrin-B gene product being critical for localizing the Na + /Ca 2+ exchanger and Na + /K + ATPase to the plasma membrane and inositol 1,4,5-trisphosphate receptor to the sarcoplasmic reticulum. 6 The study in this issue of Circulation by Smith et al 7 reports a novel human mutation in the ankyrin-B (ANK2) gene that results in recurrent ven-tricular fibrillation. It is a single amino acid substitution at a highly conserved residue p.R990Q, which locates at a spec-trin binding domain on ankyrin-B that is far upstream of the ankyrin-B C-terminal domains, where all previous mutations were identified. Although in silico modeling shows that the mutation is not on the interaction interface between ankyrin-B and βII-spectrin, binding of βII-spectrin to the mutated p.R990Q ankyrin-B is greatly impaired when tested in vitro. Therefore, the authors proposed a model in which βII-spectrin recruits ankyrin-B and targets ionophore proteins to the membrane , regulating cardiac excitability. The novelty in this finding relates to the independence of the mutation to ionophore proteins. Not only is the mutation in a cytoskeleton adaptor protein (ankyrin-B), but it affects a cytoskeletal attachment domain rather than an ion channel binding domain, much in the way that mutations in the structural protein desmopla-kin affect binding of the microtubule …