Functional analysis of hERG potassium channels and mutations underlying the Long QT Syndrome.

摘要

The Long QT Syndrome is an intricate cardiac disease in which the combination of many genetic, environmental, as well as functional and anatomic factors ultimately determine the phenotype in patients. Although many of its pathophysiologic aspects have been unraveled and have been proved useful as a paradigm for other cardiac arrhythmias, the prediction of the phenotype in asymptomatic patients at present remains problematic. In this regard, the suitability of numerous compounds with proven proficiency but that are known to cause some degree of idiosyncratic QT-prolongation is currently a matter of controversy. Moreover, at present serious anti-LQTS drugs are still lacking. Hence, these shortcomings in our knowledge still impede the selective and efficient treatment of (LQT)patients, but more importantly they also hinder the process of drug discovery and development in our strive toward better treatment for known and newly identified diseases. Hence, further 'in-vitro' studies are needed to advance our understanding of the fundamental mechanisms involved in this electrical cardiac disease.;Here, we aim at contributing to the current knowledge on the pathophysiology of the LQTS and on the biophysics of the ion channels involved. First, we investigated a peculiar combination of two unrelated LQTS cases that are caused by one p.Pro347Ser mutation in the hERG channel, but both displaying distinct phenotypes. This study focused on identifying the dysfunction underlying the phenotype, as well as on providing an explanation for the heterogeneity of the phenotype as demonstrated by both these cases.;Subsequently, our study aimed at defining the fundamental role of the p.Pro347Ser-containing region within the hERG channel, since the function of this region i.e. the proximal domain, until recently was largely unknown. Then, our interest focused on the identification of other subdomains within the N-terminus of hERG that can modulate fundamental functions of the channel like opening and closure. Since these N-terminal regions were responsible for the modulation of the gating processes, our interest was also raised toward identifying the putative receptor site(s) of those subdomains near the various structures that are important elements of the gating machinery.