Cardiac excitability is finely controlled by a combination of depolarizing and repolarizing currents. The ion channels at the source of the cardiac action potential are regulated at multiple levels. Interestingly, we have recently obtained provocative results that showed that the expression of the depolarizing sodium channel and the repolarizing potassium channel Ito, shared a common, yet to be identified, regulation mechanism. Following gene silencing of KChIP2, an accessory subunit of Ito, we found that the expression of Ito and INa was abolished producing a non-excitable cardiac myocytes. This suggested that the regulation of ion channel mediating these two major currents could be coordinated. microRNAs (miRNAs) are an abundant class of endogenous non-protein coding small RNAs which negatively regulate gene expression at the posttranscriptional level. Recent data imply that over one third of the human genome is regulated by this novel posttranscriptional mechanism involving miRNAs. Given the global effect of microRNAs on gene expression, it is not surprising that they have been implicated in diverse biological processes and pathological conditions such as cell proliferation, differentiation, apoptosis, cancer, and heart diseases. With this new emerging data in regards to the novel and powerful posttranscriptional mechanism involving miRNAs in gene regulation and based on our preliminary data which demonstrate the coordinated regulation of expression of Ito and INa through KChIP2, we hypothesize that KChIP2 acts as an 'excitability switch' which controls the expression of depolarizing (INa) and repolarizing (Ito) currents through a regulation mechanism involving miRNA(s).Together these findings would reveal a common regulatory mechanism of a depolarizing and repolarizing current which could explain the link between sodium channel mutations and the phenotypic expression of arrhythmic syndromes such as Brugada Syndrome. The role of miRNAs in cardiac ion channel regulation is very limited. If proven to be true, our hypothesis will provide us with a paradigm-shifting idea that would indicate that the expression of a complex of depolarizing and repolarizing channels might be coordinated through a common miRNA(s) regulation mechanism. Clearly understanding the regulatory mechanisms of miRNAs on cardiac ion channels in normal and diseased cardiac cells will help us distinguish which microRNAs could represent therapeutic targets for cardiac arrhythmias.
|Program type||Innovative Research Grant|
|Effective start/end date||01/01/2009 → 06/30/2010|