S100A1 deficiency results in prolonged ventricular repolarization in response to sympathetic activation.

S100A1 is a Ca(2+)-binding protein and predominantly expressed in the heart. We have generated a mouse line of S100A1 deficiency by gene trap mutagenesis to investigate the impact of S100A1 ablation on heart function. Electrocardiogram recordings revealed that after beta-adrenergic stimulation S100A1-deficient mice had prolonged QT, QTc and ST intervals and intraventricular conduction disturbances reminiscent of 2 : 1 bundle branch block. In order to identify genes affected by the loss of S100A1, we profiled the mutant and wild type cardiac transcriptomes by gene array analysis. The expression of several genes functioning to the electrical activity of the heart were found to be significantly altered. Although the default prediction would be that mRNA and protein levels are highly correlated, comprehensive immunoblot analyses of salient up- or down-regulated candidate genes of any cellular network revealed no significant changes on protein level. Taken together, we found that S100A1 deficiency results in cardiac repolarization delay and alternating ventricular conduction defects in response to sympathetic activation accompanied by a significantly different transcriptional regulation.

Pathologies involving the S100 proteins and RAGE.

The S100 proteins are exclusively expressed in vertebrates and are the largest subgroup within the superfamily of EF-hand Ca2(+)-binding proteins Generally, S100 proteins are organized as tight homodimers (some as heterodimers). Each subunit is composed of a C-terminal, 'canonical' EF-hand, common to all EF-hand proteins, and a N-terminal, 'pseudo' EF-hand, characteristic of S100 proteins. Upon Ca2(+)-binding, the C-terminal EF-hand undergoes a large conformational change resulting in the exposure of a hydrophobic surface responsible for target binding A unique feature of this protein family is that some members are secreted from cells upon stimulation, exerting cytokine- and chemokine-like extracellular activities via the Receptor for Advanced Glycation Endproducts, RAGE. Recently, larger assemblies of some S100 proteins (hexamers, tetramers, octamers) have been also observed and are suggested to be the active extracellular species required for receptor binding and activation through receptor multimerization Most S100 genes are located in a gene cluster on human chromosome 1q21, a region frequently rearranged in human cancer The functional diversification of S100 proteins is achieved by their specific cell- and tissue-expression patterns, structural variations, different metal ion binding properties (Ca2+, Zn2+ and Cu2+) as well as their ability to form homo-, hetero- and oligomeric assemblies Here, we review the most recent developments focussing on the biological functions of the S100 proteins and we discuss the presently available S100-specific mouse models and their possible use as human disease models In addition, the S100-RAGE interaction and the activation of various cellular pathways will be discussed. Finally, the close association of S100 proteins with cardiomyopathy, cancer, inflammation and brain diseases is summarized as well as their use in diagnosis and their potential as drug targets to improve therapies in the future.