Biophysical Modulation of Cardiac Ion Channels by MicroRNA

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Project Summary MicroRNAs (miRs) are evolutionally conserved small non-coding RNA molecules that are broadly involved in regulating most biological events; previous studies have focused on the canonical mRNA interference (RNAi) mechanism of miRs. During the previous funding period, we were the first to unveil an evolutionarily- conserved novel biophysical action for miRs beyond its RNAi mechanism. Specifically, we revealed a novel biophysical action of miR1, which is the most predominant miR in the heart and is downregulated in human heart failure. We found that miR1 physically binds to an inward rectifier potassium channel Kir2.1, directly suppresses the IK1 current and biophysically modulates cardiac cellular electrophysiology. Importantly, we found that a human single nucleotide polymorphism (hSNP) of miR1–– hSNP14A/G (rs776480338), in which the 14th nucleotide “A” is mutated to “G”, is a RNAi-only variant that specifically abolishes the biophysical action while maintaining the RNAi function of miR1, validating that the biophysical modulation is independent of RNAi. Our discoveries suggest that miRs modulate cardiac homeostasis through two different mechanisms: 1) canonical RNAi that regulates the expression of proteins, including ion channels, and 2) newly-discovered mechanism of direct binding with proteins that quickly results in functional modulation. With this important new finding, it is now imperative to investigate if multiple cardiac ion channels are biophysically modulated by miRs and to elucidate the specific physiological impact of miR1’s biophysical action in the regulation of cardiac (electro)physiology. Based on our published findings and preliminary data, we hypothesize that the biophysical modulation of cardiac ion channels by miRs is a general regulatory mechanism that exists broadly and plays a critical role in the homeostasis of the heart. We will study this with the following specific aims. 1) To investigate the biophysical modulation of cardiac ion channels by miR1, 2) To understand the physiological impact of miRs’ biophysical action on the heart, 3) To unveil the general mechanisms guiding miRs’ biophysical modulation of cardiac ion channels. In addition to a broad range of cellular activities regulated by the large number of miRs (>30,000 miRs in >200 species) and ion channels, our study will significantly and innovatively expand the biological significance of miR biology and ion channel biology with broad implications. Our discoveries have pioneered a new field in miR biology and will provide a mechanistic foundation and new avenue of RNA-medicine development for antiarrhythmic therapy.