title: Estrogen regulation of the transient outward K(+) current involves estrogen receptor α in mouse heart.
abstract: OBJECTIVE
  We have previously shown that androgens upregulate cardiac K(+) channels and shorten repolarization. However, the effects that estrogens (E2) and estrogen receptors (ER) might have on the various repolarizing K(+) currents and underlying ion channels remain incompletely understood. Accordingly, our objective was to verify whether and how E2 and its ERs subtypes influence these K(+) currents.
  
  
  RESULTS
  In order to examine the influence of E2 and ERs on K(+) currents we drastically lowered the E2 level through ovariectomy (OVX; 74% reduction vs CTL) and in parallel, we used female mice lacking either ERα (ERαKO) or ERβ (ERβKO). In OVX mice, results showed a specific increase of 35% in the density of the Ca(2+)-independent transient outward K(+) current (Ito) compared to CTL. Western blots showed increase in Kv4.2 and Kv4.3 sarcolemmal protein expression while qPCR revealed higher mRNA expression of only Kv4.3 in OVX mice. This upregulation of Ito was correlated with a shorter ventricular action potential duration and QTc interval. In ERαKO but not ERβKO mice, the mRNA of Kv4.3 was selectively increased. Furthermore, when ventricular myocytes obtained from ERαKO and ERβKO were cultured in the presence of E2, results showed that E2 reduced Ito density only in ERβKO myocytes confirming the repressive role of E2-ERα in regulating Ito.
  
  
  CONCLUSIONS
  Altogether, these results suggest that E2 negatively regulates the density of Ito through ERα, this highlights a potential role for this female hormone and its α-subtype receptor in modulating cardiac electrical activity.
authors.affiliation: Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada. Electronic address: gracia.el.gebeily@umontreal.ca.
authors.forename: Gracia
authors.initials: G
authors.lastname: El Gebeily
authors.affiliation: Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, Canada; Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada. Electronic address: nabil.el.khoury@umontreal.ca.
authors.forename: Nabil
authors.initials: N
authors.lastname: El Khoury
authors.affiliation: Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada. Electronic address: sophie.mathieu@umontreal.ca.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada. Electronic address: judith.brouillette@umontreal.ca.
authors.forename: Judith
authors.initials: J
authors.lastname: Brouillette
authors.affiliation: Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, Canada; Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada. Electronic address: celine.fiset@icm-mhi.org.
authors.forename: Céline
authors.initials: C
authors.lastname: Fiset
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics; D004967:Estrogens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000096:biosynthesis; D051672:Shal Potassium Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D002118:Calcium
keywords: Estrogen; Estrogen receptor; Mouse; Potassium currents; Ventricle