A microtranslatome coordinately regulates sodium and potassium currents in the human heart.

Catherine A Eichel,Gail A Robertson,Margaret B Jameson,Fang Liu,Erick B Ríos-Pérez,David K Jones,Jennifer J Knickelbine

doi:10.7554/elife.52654

Catherine A Eichel, Gail A Robertson + Show 5 more

Open Access

https://doi.org/10.7554/elife.52654

Copy DOI

Journal: eLife	Publication Date: Oct 31, 2019
Citations: 26	License type: CC BY 4.0

Affiliation: University of Wisconsin–Madison

Abstract

Catastrophic arrhythmias and sudden cardiac death can occur with even a small imbalance between inward sodium currents and outward potassium currents, but mechanisms establishing this critical balance are not understood. Here, we show that mRNA transcripts encoding INa and IKr channels (SCN5A and hERG, respectively) are associated in defined complexes during protein translation. Using biochemical, electrophysiological and single-molecule fluorescence localization approaches, we find that roughly half the hERG translational complexes contain SCN5A transcripts. Moreover, the transcripts are regulated in a way that alters functional expression of both channels at the membrane. Association and coordinate regulation of transcripts in discrete 'microtranslatomes' represents a new paradigm controlling electrical activity in heart and other excitable tissues.

Highlights

Signaling in excitable cells depends on the coordinated flow of inward and outward currents through a defined ensemble of ion channel species
The association occurred in HEK293 cells, where additional controls showed that the antibodies used did not interact nonspecifically with mRNA encoding the other ion channels or subunits (Figure 1—figure supplement 1)
This experiment demonstrates that transcripts encoding hERG1a, hERG1b and Nav1.5 physically interact within the cell and can be copurified using antibodies targeting either hERG1a or Nav1.5 nascent proteins

Summary

Introduction

Signaling in excitable cells depends on the coordinated flow of inward and outward currents through a defined ensemble of ion channel species. This is especially true in heart, where the expression of many different ion channels controls the spread of excitation triggering the concerted contraction of the ventricular myocardium. Because current magnitude is greater in heteromeric hERG1a/1b vs homomeric hERG1a channels, and loss of hERG1b is proarrhythmic (Sale et al, 2008; Jones et al, 2014), the mechanism of cotranslational assembly of hERG subunits is important in cardiac repolarization (Liu et al, 2016)

Methods

Results

Conclusion