Activation of Notch signaling by short-term treatment with Jagged-1 enhances store-operated Ca2+ entry in human pulmonary arterial smooth muscle cells

Hisao Yamamura, Aya Yamamura, Eun A. Ko, Nicole M. Pohl, Kimberly A. Smith, Amy Zeifman, Frank L. Powell, Patricia A. Thistlethwaite, Jason X.J. Yuan

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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 Ca2+ 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 Ca2+ 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 Ca2+ channels (SOC may be involved in the Jag-1-mediated enhancement of SOCE in human PASMC.

Original languageEnglish (US)
Pages (from-to)C871-C878
JournalAmerican Journal of Physiology - Cell Physiology
Issue number9
StatePublished - May 1 2014
Externally publishedYes


  • Jagged
  • Notch intracellular domain
  • Notch receptor
  • Pulmonary artery
  • Smooth muscle
  • Store-operated calcium entry

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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