ATP-induced mitogenesis is mediated by cyclic AMP response element-binding protein-enhanced TRPC4 expression and activity in human pulmonary artery smooth muscle cells

Shen Zhang, Carmelle V. Remillard, Ivana Faniozzi, Jason X.J. Yuan

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

Extracellular ATP and intracellular cyclic AMP response element-binding protein (CREB, a transcription factor) promote cell proliferation in many cell types. The canonical transient receptor potential (TRPC) channels, which putatively participate in forming store- and receptor-operated Ca2+ channels, have been implicated in the pulmonary vascular remodeling processes. A link between extracellular ATP, CREB activation, and TRPC4 channel expression and activity has not been shown in human pulmonary artery smooth muscle cells (PASMC). Long-term (24-48 h) treatment of human PASMC with a low dose (100 μM) of ATP, which did not trigger a transient rise in free cytosolic Ca 2+ concentration ([Ca2+]i) when applied acutely to the cells, caused marked increases in CREB phosphorylation and TRPC4 protein expression. The time course indicated that the ATP-mediated CREB phosphorylation preceded TRPC4 upregulation, whereas transfection of a non-phosphorylatable CREB mutant abolished ATP-mediated TRPC4 expression. Furthermore, treatment of human PASMC with ATP also enhanced the amplitude of capacitative Ca2+ entry (CCE) induced by passive store depletion, whereas the small interfering RNA specifically targeting TRPC4 attenuated ATP-mediated increases in TRPC4 expression and CCE amplitude and inhibited ATP-induced PASMC proliferation. These data suggest that low-dose ATP exerts part of its mitogenic effect in human PASMC via CREB-mediated upregulation of TRPC4 channel expression and activity and the subsequent increase in CCE and [Ca2+]i.

Original languageEnglish (US)
Pages (from-to)C1192-C1201
JournalAmerican Journal of Physiology - Cell Physiology
Volume287
Issue number5 56-5
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

Keywords

  • Capacitative Ca entry
  • Proliferation
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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