title: Endothelin-1 stimulates the expression of L-type Ca2+ channels in neonatal rat cardiomyocytes via the extracellular signal-regulated kinase 1/2 pathway.
abstract: The cardiac L-type Ca(2+) channel current (I(Ca,L)) plays an important role in controlling both cardiac excitability and excitation-contraction coupling and is involved in the electrical remodeling during postnatal heart development and cardiac hypertrophy. However, the possible role of endothelin-1 (ET-1) in the electrical remodeling of postnatal and diseased hearts remains unclear. Therefore, the present study was designed to investigate the transcriptional regulation of I(Ca,L) mediated by ET-1 in neonatal rat ventricular myocytes using the whole-cell patch-clamp technique, quantitative RT-PCR and Western blotting. Furthermore, we determined whether the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is involved. ET-1 increased I(Ca,L) density without altering its voltage dependence of activation and inactivation. In line with the absence of functional changes, ET-1 increased L-type Ca(2+) channel pore-forming α1C-subunit mRNA and protein levels without affecting the mRNA expression of auxiliary β- and α2/δ-subunits. Furthermore, an actinomycin D chase experiment revealed that ET-1 did not alter α1C-subunit mRNA stability. These effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 but not the ETB receptor antagonist BQ-788. Moreover, the effects of ET-1 on I(Ca,L) and α1C-subunit expression were abolished by the ERK1/2 inhibitor (PD98059) but not by the p38 MAPK inhibitor (SB203580) or the c-Jun N-terminal kinase inhibitor (SP600125). These findings indicate that ET-1 increased the transcription of L-type Ca(2+) channel in cardiomyocytes via activation of ERK1/2 through the ETA receptor, which may contribute to the electrical remodeling of heart during postnatal development and cardiac hypertrophy.
authors.affiliation: Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, Peoples Republic of China. ylz7210281034@163.com
authors.forename: Liangzhu
authors.initials: L
authors.lastname: Yu
authors.forename: Mincai
authors.initials: M
authors.lastname: Li
authors.forename: Tonghui
authors.initials: T
authors.lastname: She
authors.forename: Chunrong
authors.initials: C
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: Banghua
authors.initials: B
authors.lastname: Wang
authors.forename: Menglin
authors.initials: M
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000873:Anthracenes; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D011725:Pyridines; C432165:pyrazolanthrone; C086539:BQ 788; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093642:SB 203580; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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