Rififylin (RFFL), a Novel Regulator of Transient Outward (Ito) Potassium Channels

Abstract

The expression of sarcolemmal ion channels is a net result of the rate of coordinated biosynthesis, proper folding, forward trafficking, recycling, and degradation. The importance of these processes was highlighted by several genome‐wide association studies that reported novel loci that modify the QT interval and are located in or near genes involved in protein trafficking and degradation (Roder et al., 2014; Roder et al. 2018). One of the genes identified, the ring finger and FYVE‐like domain containing E3 ubiquitin protein ligase rififylin (RFFL), has also been shown to regulate cardiac excitation and growth in a congenic rat strain (Gopalakrishnan et al. 2011). As transient outward K+ currents (Ito) are essential during the whole repolarization phase of the action potential in rodents, we hypothesized that RFFL could regulate cardiac excitation through Ito‐encoding channels. Adult rabbit cardiomyocytes with adenovirus‐expressed RFFL exhibited reduced Ito,f. In HEK cells, transient RFFL overexpression caused polyubiquitination and downregulation of total and surface levels of Kv4.2 and Kv4.3 as well as the corresponding current Ito,f. In contrast, in transiently co‐transfected HEK cells, overexpressed RFFL monoubiquitinated and upregulated total and membrane levels of Kv1.4 and the corresponding current Ito,s in a RING domain‐dependent manner. We conclude that RFFL, through its interactions with and ubiquitination of Ito‐encoding channels Kv4.2, Kv4.3 and Kv1.4 regulate their forward trafficking and degradation, which may affect cardiac action potential shape and duration.Support or Funding InformationNHLBI grant 5R01HL134706‐02 (GK).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.