Cytoskeletal Basis of Ion Channel Function in Cardiac Muscle

Abstract

SummaryThe heart is a force-generating organ that responds to self-generated electrical stimuli from specialized cardiomyocytes. This function is modulated by sympathetic and parasympathetic activity.In order to contract and accommodate the repetitive morphological changes induced by the cardiac cycle, cardiomyocytes depend on their highly evolved and specialized cytoskeletal apparatus. Defects in components of the cytoskeleton, in the long term, affect the ability of the cell to compensate at both functional and structural levels. In addition to the structural remodeling, the myocardium becomes increasingly susceptible to altered electrical activity leading to arrhythmogenesis. The development of arrhythmias secondary to structural remodeling defects has been noted, although the detailed molecular mechanisms are still elusive. Here I will review the current knowledge of the molecular and functional relationships between the cytoskeleton and ion channels and, I will discuss the future impact of new data on molecular cardiology research and clinical practice.

S38G single-nucleotide polymorphism at the KCNE1 locus is associated with heart failure

“…Indeed, it has been reported that the biomechanical stress during myocardium contraction-relaxation cycles may contribute to determining an altered ion channel localization, thus possibly influencing the ionic properties of cardiac tissue. 17,18 An SNP in the KCNE1 gene (A to G at position 112), leading to a glycine substitution for serine at amino acid position 38, has been identified. 19 The functional significance of the S38G polymorphism in the KCNE1 gene remains unclear.…”

The Role of Late I Na in Development of Cardiac Arrhythmias

“…Mutations in scaffolding and/or cytoskeletal “channel interaction proteins” (ChIPs) are recognized causes of LQT syndrome (Ackerman and Mohler 2010). Mutations in caveolin-3 (Vatta et al 2006), alpha-1 syntrophin (Ueda et al 2008; Wu et al 2008a), and β IV spectrin (Hund et al 2010; Wu et al 2008a; Sarhan et al 2009; Vatta and Faulkner 2006) are associated with increased magnitude of late I Na and with LQT and/or SIDS. Proteins such as F-actin, telethonin, α-actinin-2, and Z-band alternatively spliced PDZ-motif (ZASP) that are anchored at the Z-line may participate in the trafficking of ion channels to the T-tubule membrane (Vatta and Faulkner 2006).…”

“…Mutations in caveolin-3 (Vatta et al 2006), alpha-1 syntrophin (Ueda et al 2008; Wu et al 2008a), and β IV spectrin (Hund et al 2010; Wu et al 2008a; Sarhan et al 2009; Vatta and Faulkner 2006) are associated with increased magnitude of late I Na and with LQT and/or SIDS. Proteins such as F-actin, telethonin, α-actinin-2, and Z-band alternatively spliced PDZ-motif (ZASP) that are anchored at the Z-line may participate in the trafficking of ion channels to the T-tubule membrane (Vatta and Faulkner 2006). A mutation in telethonin is reported to increase Na + window current (Mazzone et al 2008), and a missense mutation in ZASP shifts the voltage dependence of Na + channel activation (Li et al 2010).…”

A ZASP Missense Mutation, S196L, Leads to Cytoskeletal and Electrical Abnormalities in a Mouse Model of Cardiomyopathy

“…2 Site-directed mutagenesis of the S196L mutation in the ZM4 motif was performed as previously described. …”

“…Replacement of deranged myocardium by fibrous tissues has been proposed as a likely mechanism of reentrant tachycardia and/or conduction disease, but very little is known about the cellular mechanisms connecting cytoskeletal alterations to arrhythmias in DCM. 2 …”