2011
DOI: 10.1074/jbc.m110.198853
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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… Show more

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Cited by 37 publications
(32 citation statements)
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“…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.…”
Section: Drug-induced Trafficking Inhibition 207mentioning
confidence: 48%
“…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.…”
Section: Drug-induced Trafficking Inhibition 207mentioning
confidence: 48%
“…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].…”
Section: Discussionmentioning
confidence: 79%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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).…”
mentioning
confidence: 99%