title: 17 beta-estradiol modulates expression of low-voltage-activated Ca(V)3.2 T-type calcium channel via extracellularly regulated kinase pathway in cardiomyocytes.
abstract: T-type Ca(2+) channel current (I(Ca,T)) plays an important role for spontaneous pacemaker activity and is involved in the progression of structural heart diseases. Estrogens are of importance for the regulation of growth and differentiation and function in a wide array of target tissues, including those in the cardiovascular system. The aim of this study was to elucidate the short-term and long-term effects of 17beta-estradiol (E(2)) on I(Ca,T) in cardiomyocytes. We employed in vivo and in vitro techniques to clarify E(2)-mediated modulation of heart rate (HR) in ovariectomized rats and I(Ca,T) in cardiomyocytes. Ovariectomy increased HR and E(2) supplement reduced HR in ovariectomized rats. Slowing of E(2)-induced HR was consistent with the deceleration of automaticity in E(2)-treated neonatal cardiomyocytes. Short-term application of E(2) did not have significant effects on I(Ca,T), whereas in cardiomyocytes treated with 10 nm E(2) for 24 h, estrogen receptor-independent down-regulation of peak I(Ca,T) and declination of Ca(V)3.2 mRNA were observed. Expression of a cardiac-specific transcription factor Csx/Nkx2.5 was also suppressed by E(2) treatment for 24 h. On the other hand, expression of Ca(V)3.1 mRNA was unaltered by E(2) treatment in this study. An ERK-1/2, 5 inhibitor, PD-98059, abolished the effects of E(2) on I(Ca,T) and Ca(V)3.2 mRNA as well as Csx/Nkx2.5 mRNA. These findings indicate that E(2) decreases Ca(V)3.2 I(Ca,T) through activation of ERK-1/2, 5, which is mediated by the suppression of Csx/Nkx2.5-dependent transcription, suggesting a genomic effect of E(2) as a negative chronotropic factor in the heart.
authors.affiliation: Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, Japan.
authors.forename: Farzana
authors.initials: F
authors.lastname: Marni
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Masaki
authors.initials: M
authors.lastname: Morishima
authors.forename: Toru
authors.initials: T
authors.lastname: Shimaoka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Uchino
authors.forename: Mingqi
authors.initials: M
authors.lastname: Zheng
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kaku
authors.forename: Katsushige
authors.initials: K
authors.lastname: Ono
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D004958:Estradiol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy / Q000662:veterinary; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C509958:Cacna1h protein, rat; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger; D004958:Estradiol; D048049:Extracellular Signal-Regulated MAP Kinases