Transcription factors for ion channels: active or passive players in cardiac remodeling?

Chronic cardiac disease is associated with structural, mechanical, and electrical remodeling processes that comprise activation of numerous signal transduction pathways [1]. In hypertrophy and heart failure, for instance, electrical remodeling consists of prolongation of the ventricular action potential duration that may be interpreted as an acquired long-QT syndrome and hence may explain the propensity for ventricular arrhythmias. In myocardial biopsies from these patients, the transient outward current I to is significantly down-regulated and this is associated with a lower expression of mRNA for the corresponding ion channel subunits (in man predominantly Kv4.3, in rat predominantly Kv4.2; Ref. [2]). Despite the clinical relevance of I to reduction, the molecular mechanisms regulating ion channel expression in cardiac diseases are currently unknown. Traditionally, a certain number and species of ion channels within the membrane are considered responsible for the cell type-specific shape of the action potential; however, ion channel numbers should be viewed as highly dynamic. Channel expression can be regulated at multiple cellular levels, i.e. mRNA transcription, altered rates of protein translation, posttranslational protein modifications, changes in membrane trafficking and insertion, and phosphorylation of channel proteins. Regulation of transcription requires regulatory factors that activate or suppress gene expression. These transcription factors bind to certain DNA sequences within the … *Tel.: +49-351-458-6279; fax: +49-351-458-6315. Email address: dobrev{at}rcs.urz.tu-dresden.de