title: Activation of Notch signaling by short-term treatment with Jagged-1 enhances store-operated Ca(2+) entry in human pulmonary arterial smooth muscle cells.
abstract: Notch signaling plays a critical role in controlling proliferation and differentiation of pulmonary arterial smooth muscle cells (PASMC). Upregulated Notch ligands and Notch3 receptors in PASMC have been reported to promote the development of pulmonary vascular remodeling in patients with pulmonary arterial hypertension (PAH) and in animals with experimental pulmonary hypertension. Activation of Notch receptors by their ligands leads to the cleavage of the Notch intracellular domain (NICD) to the cytosol by γ-secretase; NICD then translocates into the nucleus to regulate gene transcription. In this study, we examined whether short-term activation of Notch functionally regulates store-operated Ca(2+) entry (SOCE) in human PASMC. Treatment of PASMC with the active fragment of human Jagged-1 protein (Jag-1) for 15-60 min significantly increased the amplitude of SOCE induced by passive deletion of Ca(2+) from the intracellular stores, the sarcoplasmic reticulum (SR). The Jag-1-induced enhancement of SOCE was time dependent: the amplitude was maximized at 30 min of treatment with Jag-1, which was closely correlated with the time course of Jag-1-mediated increase in NICD protein level. The scrambled peptide of Jag-1 active fragment had no effect on SOCE. Inhibition of γ-secretase by N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) significantly attenuated the Jag-1-induced augmentation of SOCE. In addition to the short-term effect, prolonged treatment of PASMC with Jag-1 for 48 h also markedly enhanced the amplitude of SOCE. These data demonstrate that short-term activation of Notch signaling enhances SOCE in PASMC; the NICD-mediated functional interaction with store-operated Ca(2+) channels (SOC) may be involved in the Jag-1-mediated enhancement of SOCE in human PASMC.
authors.affiliation: Department of Medicine, Institute for Personalized Respiratory Medicine, Department of Pharmacology; Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois;
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamura
authors.forename: Eun A
authors.initials: EA
authors.lastname: Ko
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Pohl
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Smith
authors.forename: Amy
authors.initials: A
authors.lastname: Zeifman
authors.forename: Frank L
authors.initials: FL
authors.lastname: Powell
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thistlethwaite
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051880:Receptors, Notch / Q000819:agonists* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D013997:Time Factors
chemical_list: D002120:Calcium Channel Agonists; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D010446:Peptide Fragments; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D053829:Amyloid Precursor Protein Secretases
keywords: Jagged; Notch intracellular domain; Notch receptor; pulmonary artery; smooth muscle; store-operated calcium entry