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- W4319931852 abstract "The strong inward-rectifying subclass of potassium channel Kir2.1 produces IK1 current in the human myocardium which stabilizes the resting membrane potential of the heart and shapes the cardiac action potential. Perturbation or disruption of IK1 is associated with various arrhythmic phenotypes. Multiple studies have provided extensive evidence for the modulation of potassium channels by endogenous regulatory proteins. This group has studied extensively the relationship between the small ubiquitin-like modifier SUMO and Kir2.1 biophysical properties. Using patch clamp and Förster resonance energy transfer (FRET) studies in heterologous cells and rat ventricular cardiomyocytes (RVCM), we have demonstrated that SUMO interacts with Kir2.1 at a key lysine residue K49; the proximate physical association of which SUMO associates with the channel interferes with the binding pocket for phosphatidylinositol bisphosphate 2 (PIP2) required for channel gating, resulting in decreased IK1 current. Recent studies have posited an important role for another ubiquitin-like modifier, FAT10 in the regulation of ion channels that are expressed in the myocardium. While our group has characterized that acute hypoxia inhibits IK1 current in RVCM by an increased SUMOylation mechanism, another group has shown that FAT10 expression is markedly increased in hypoxia RVCMs. Together with studies showing evidence of competition for common target proteins between SUMO and FAT10, we seek to elucidate a mechanism of FAT10ylation of Kir2.1. Using FRET, we show disrupted SUMOylation in the presence of FAT10 in the heterologous cell system. Using electrophysiological techniques, we also demonstrate a change in Kir2.1 channel dynamics when FAT10 is co-expressed in both Xenopus laevis oocytes and HEK293T cells. Lastly, this work establishes a foundation for the study of Kir2.1 channel FAT10ylation in the native cardiomyocyte system in which FAT10 is posited to have a cardioprotective effect." @default.
- W4319931852 created "2023-02-11" @default.
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- W4319931852 date "2023-02-01" @default.
- W4319931852 modified "2023-09-25" @default.
- W4319931852 title "Regulation of Kir2.1 channels by ubiquitin-like modifier proteins" @default.
- W4319931852 doi "https://doi.org/10.1016/j.bpj.2022.11.2107" @default.
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