Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/23702
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dc.titleSex hormones regulate HERG K+ channel trafficking and function
dc.contributor.authorWU ZHIYUAN
dc.date.accessioned2011-06-30T18:00:36Z
dc.date.available2011-06-30T18:00:36Z
dc.date.issued2010-07-26
dc.identifier.citationWU ZHIYUAN (2010-07-26). Sex hormones regulate HERG K+ channel trafficking and function. ScholarBank@NUS Repository.
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/23702
dc.description.abstractThe long QT syndrome (LQTS), which is characterized as prolongation of QT intervals, is an inherited and acquired channelopathy associated with sudden cardiac death due to ventricular arrhythmias. Malfunction of human ether-a-go-go-related gene (HERG) encoded K+ channel is one of the major causes of LQTS. In the first chapter of this thesis, the physiology of HERG channel including the structure, unique gating and biosynthesis, was reviewed. Then, recent progress on regulatory effects of sex hormones on HERG current was summarized. Proarrhythmic drugs induce torsade de pointes more frequently in women than men. To reveal the mechanism for the gender differences in QT interval and acquired LQTS, I first investigated the effect of androgen and estrogen on HERG proteins. It was found that treatment with estrogen failed to affect HERG channel expression. In contrast, androgens increased HERG protein abundance in the presence of cardiac androgen receptor variant (AR45), but not full length androgen receptor. Confocal microscopy showed that the upregulated HERG proteins were seen in the ER, Golgi complex and plasma membrane without clear preferential colocalization. Chronic androgen treatment also increased HERG K+ current density in the presence of AR45. Moreover, 5a-DHT increased ERG protein abundance in isolated rabbit cardiac myocytes. The upregulation of HERG protein was due to inhibition of channel degradation, instead of enhancing channel synthesis. In addition, 5a-DHT/AR45 signaling induced phosphorylation of extracellular signaling regulated kinase (ERK1/2). Blockade of ERK1/2 prevented the effect of androgen on HERG protein abundance. In conclusion, these data provide evidence that stimulation of AR45 receptors by androgens upregulates HERG K+ channel abundance and activity mainly through stabilizing xi HERG protein in an ERK1/2 dependent mechanism and suggest a mechanism to explain the sex difference in the long QT syndrome. Progesterone level increases steadily during pregnancy, and reaches ?mol/L level before the delivery. The second part of my work was to investigate the effect of progesterone on HERG channel function. It was found that chronic progesterone treatment decreased the abundance of mature HERG channel in rat neonatal cardiac myocytes and HERG-HEK293 cells. Progesterone also concentration-dependently decreased HERG current density. Immunofluoresence microscopy shows that progesterone preferentially decreased HERG channel protein abundance in the plasma membrane, induced protein accumulation in the dilated ER. Application of sterol binding agent or over-expression of Rab9 rescued the progesterone-induced HERG trafficking defect. Disturbance of intracellular cholesterol homeostasis mimicked the effect of progesterone on HERG channel trafficking. Progesterone may impair HERG channel folding in the ER and/or block its trafficking to the Golgi complex by disrupting intracellular cholesterol homeostasis. This finding may reveal a novel molecular mechanism to explain the QT prolongation during late pregnancy. In conclusion, this thesis examined how sex hormones regulate HERG K+ channels with a combination of pharmacological manipulations, confocal microscopy, molecular biology and electrical physiology. This study not only provides a molecular mechanism for the sex differences in QT intervals and drug-induced arrhythmias but also explains the longer QT interval during late pregnancy and the high risk of arrhythmias development in the fetus.
dc.language.isoen
dc.subjectHERG, androgen, AR45, progesterone, trafficking
dc.typeThesis
dc.contributor.departmentPHARMACOLOGY
dc.contributor.supervisorBIAN JINSONG
dc.contributor.supervisorDAWE, GAVIN STEWART
dc.description.degreePh.D
dc.description.degreeconferredDOCTOR OF PHILOSOPHY
dc.identifier.isiutNOT_IN_WOS
Appears in Collections:Ph.D Theses (Open)

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