Progesterone Impairs Human Ether-a-go-go-related Gene (HERG) Trafficking by Disruption of Intracellular Cholesterol Homeostasis

Abstract

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...

Molecular Determinants of Pentamidine-Induced hERG Trafficking Inhibition

“…Furthermore, we provide the first example of a therapeutic compound that arrests hERG maturation in a nonexportable form via binding to residues in the canonical drug-binding site of hERG. This is very different from what has been proposed for proarrhythmic compounds such as probucol or progesterone (Guo et al, 2011;Wu et al, 2011), which are thought to mediate changes in hERG surface expression via effects on the composition of lipid rafts surrounding the channel protein. The reliance of pentamidine on hERG-specific amino acid residues may also provide an answer to its specificity and may explain why pentamidine effects are restricted to ER export, because the native conformation of hERG that is present in post-ER compartments binds pentamidine with much lower affinity only.…”

High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition

“…3C and D). Taken together, these data demonstrate that the high-glucose-induced trafficking A trafficking deficiency in the hERG channel is activated through the ER stress response [23][24][25]. The UPR, which indicates the occurrence of an ER stress response, increases the synthesis of chaperone proteins and prevents the accumulation of unfolded protein in the ER [26,27].…”

Uterine endoplasmic reticulum stress-unfolded protein response regulation of gestational length is caspase-3 and -7–dependent

“…There is also evidence for the action of P4 and the PR in upregulating the ERSR (14,15). Indeed, pregnant mice treated with P4 2 mg/d from E13 to term demonstrated increased DDIT3 levels across gestation, resulting in increased CASP3 activation and reduced GJA1 levels (Fig.…”

“…A prolonged and/or excessive ERSR has been implicated in potentiating increased CASP3 and 7 activation (11). In every pregnancy, the uterus experiences physiological and biochemical stimuli that in other biological systems trigger an ERSR, including stretch (12), inflammation (13), hormone fluctuations (14,15), hypoxia (16), hyperplasia (17), hypertrophy (18), and demand for metabolic fuels (19).…”