Pairwise biosynthesis establishes ion channel balance and mitigates arrhythmia.

Abstract

The coordinated expression of ion channels at the plasma membrane of cells underlies cardiac rhythms, neural signaling, cell cycle progression, and a host of other physiological processes involving every cell and tissue type in the body. Perturbation of this balance results in disease, yet the underlying mechanisms of physiological control are poorly understood. Here we examined ion channel expression from transcriptomics to translation. Using human myocardium and cardiomyocytes derived from induced pluripotent stem cells, we report that the expression of ion channel transcripts encoding components of the ventricular action potential is highly correlated. We showed that ion channels are synthesized as heterotypic pairs from discrete, interacting mRNA molecules through single-molecule fluorescence techniques and biochemical and electrophysiological approaches. Remarkably, targeted depletion of one species concomitantly reduced expression of the others and mitigated proarrhythmic behavior that would otherwise arise from the selective reduction of a single channel species. We propose that, on the background of coarse regulation of the transcriptome, pairwise mRNA assemblies, or microtranslatomes, confer stability through tandem biosynthesis and coregulation of electrically complementary ion channels mediating cardiac repolarization. Such assemblies may be a general mechanism determining the composition of macromolecular complexes where the quantitative balance of components is essential to function.