4. The Role of Glycosylation in Cardiac Arrhythmias

Long QT syndrome (LQTS) is a debilitating cardiac arrhythmia, and mutations or malfunctions in the human ether-a-go-go–related gene (hERG) are the most common cause of LQTS. hERG is responsible for the cardiac potassium current (IKr), which is important for cardiac repolarization. It has 6 transmembrane domains, ranging from S1 to S6, and a complex N-linked oligosaccharide chain resides on the extracellular S5 pore linker region. The role of this glycosylation chain in hERG function has not yet been well distinguished and in the current study we aim to investigate the relationship between hERG protease susceptibility and the presence of the glycosylation chain. Using molecular techniques, we demonstrate that de-glycosylated hERG channels are degraded by the serine protease Proteinase K at a much faster rate than their glycosylated counter parts. Additionally, through removal of the end-chain sialic acid residues using the enzyme neuraminidase, we conclude that it is likely the physical blockade of susceptible protease sites that grants wild type hERG this glycosylation-dependent protection as opposed to charge repulsion facilitated by specific sugars in the carbohydrate chain. Our data show that the glycosylation chain found on hERG plays a role in protecting the channel from protease degradation, and could provide valuable insight into the development of the cardiac arrhythmia Long QT Syndrome.