Grant: Operating Grant

The Long QT Syndrome (LQTS) is an electrical disorder of the heart, which is associated with abnormal cardiac rhythms and sudden death. The LQTS 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 LQT2, has been related to the abnormal function of the hERG (Human Ether-a-go-go Related Gene) protein that forms a channel in the cell membrane channel. This channel allows potassium ions to enter the cell thereby terminating the electrical excitation of the ventricles. When the amount of potassium molecules moving through hERG channels is decreased there is a delay in the time to the termination of electrical excitation which delays the T-wave, thereby causing LQT2. This channel is important because it binds many drugs readily and therefore the Federal Drug Administration in the U.S, requires that all new drugs are screened against hERG. One important and poorly understood problem is the quality control mechanisms that regulate the levels of hERG channels at the cell membrane. The first mechanism is related to the maturation of this protein that takes place at the endoplasmic reticulum. The quality control is related to the removal of mutated and improperly folded hERG channels. A second mechanism involves the removal of hERG channels from the cell membrane that become destabilized. This includes mutated hERG channels, drug modified hERG channels and hERG channels influenced by levels of potassium ions in cells. In our study, we will evaluate the 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 of many drugs and inherited mutations involved in clinically relevant cases of the LQT2.