Grant: Project Grant

The Long QT Syndrome (LQTS) is an electrical disorder of the heart, which is associated with abnormal cardiac rhythms and sudden death. The QT interval is determined by measuring the interval between the QRS complex and the T-wave on the electrocardiograph. One form of this syndrome, referred to as LQTS2, has been related to mutations of a protein called hERG (Human Ether-a-go-go Related Gene) that reduces the function of the hERG channel in the cell membrane. This channel also binds many drugs readily, which can cause sudden death, and therefore the U.S.A. Federal Drug Administration requires that new drugs are tested against hERG. However, the mechanisms that regulate the levels of hERG channels at the cell membrane are not well understood. The first mechanism is related to the removal of mutated and improperly folded hERG channels at the endoplasmic reticulum. A second mechanism involves the removal of hERG channels from the cell membrane that become destabilized. We discovered that there are two distinct cell membrane quality control systems, the more recent of which we have little information. Also, we screened a library of drugs and small molecules and found two compounds that can stabilize mutant hERG channels at the cell membrane, which could have potential therapeutic benefits. The nature of this mechanism also is not understood and will be the subject of further investigation. In our study, we will continue to evaluate the quality control and pharmacological modulation of hERG channels using a variety of techniques that involve electrophysiology, molecular biology and advanced microscopy. We believe that this quality control mechanism will provide a new explanation for the effects involved in clinically relevant cases of LQTS2.