The prolongation of QT intervals in both mothers and fetuses during the later period of pregnancy implies that higher levels of progesterone may regulate the function of the human ether-ago-go-related gene (HERG) potassium channel, a key ion channel responsible for controlling the length of QT intervals. Here, we studied the effect of progesterone on the expression, trafficking, and function of HERG channels and the underlying mechanism. Treatment with progesterone for 24 h decreased the abundance of the fully glycosylated form of the HERG channel in rat neonatal cardiac myocytes and HERG-HEK293 cells, a cell line stably expressing HERG channels. Progesterone also concentration-dependently decreased HERG current density, but had no effect on voltage-gated L-type Ca Progesterone (P4) 2 is an important steroid hormone involved in the female menstrual cycle, pregnancy, and embryogenesis. In the normal menstrual cycle, P4 levels increase from 0.6 -4.5 nmol/liter during the preovulatory phase to 10.5-80 nmol/liter during the luteal phase (1). It was reported that P4 at Ͻ100 nmol/liter, which is comparable with that occurring during the luteal phase, had no significant effect on the QT interval (2-4). However, recent studies show that P4 may shorten the action potential duration or QT interval (5). This is probably because P4 at this level enhances the rapid component of the delayed rectifier K ϩ current and inhibits L-type Ca 2ϩ currents (6). If pregnancy occurs, P4 levels are initially maintained at the luteal level, but may increase to 1 mol/liter at term (7). Elevated levels of P4 are important for the implantation of the embryo and the maintenance of a conducive environment for the embryo. At such a high level, the corrected QT interval is significantly prolonged (8, 9). This explains why pregnant women are more susceptible to ventricular arrhythmias during pregnancy, labor, and delivery (10 -12). However, it is interesting to note that in the patients with inherited long QT syndrome (LQTS) the risk for cardiac events is not higher during pregnancy than during other periods in life (10, 13). These findings suggest that the mechanisms for pregnancy-induced cardiac events in normal healthy women are different from those in the patients with inherited LQTS.In the fetus, the P4 level was reported to be very high (ϳ4.5 mol/liter) in umbilical cord vein during late stages of pregnancy (7). At this stage, longer QT and corrected QT intervals were reported in fetal magnetocardiography and noninvasive fetal electrocardiography (14, 15). More importantly, the rate of sudden death is higher in the uterus than at most other times in the human life cycle. Although the major reasons remain unknown, several studies of newborns suggest that QT prolongation and the increased risk of ventricular arrhythmias may account for the significant mortality (16,17). This may be the same for stillbirth as several case reports indicate that LQTS is one cause for otherwise unexplained fetal demise (18).The human ether-a-go-go-related gene (HE...