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ATP-induced mitogenesis is mediated by cyclic AMP response element-binding protein-enhanced TRPC4 expression and

Shen Zhang1, Carmelle V Remillard, Ivana Fantozzi

  • 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0725, USA. xiyuan@ucsd.edu

American Journal of Physiology. Cell Physiology
|July 2, 2004
PubMed

Insights

Low-dose extracellular ATP promotes human pulmonary artery smooth muscle cell proliferation by activating CREB (cyclic AMP response element-binding protein), upregulating TRPC4 channels, and increasing calcium influx.

Area of Science:

  • Cardiovascular Biology
  • Cell Physiology
  • Molecular Signaling

Background:

  • Extracellular ATP and CREB (cyclic AMP response element-binding protein) are known to promote cell proliferation.
  • TRPC (transient receptor potential) channels are involved in pulmonary vascular remodeling.
  • The specific link between extracellular ATP, CREB, and TRPC4 in human pulmonary artery smooth muscle cells (PASMC) was previously unestablished.

Purpose of the Study:

  • To investigate the role of extracellular ATP in human PASMC proliferation.
  • To elucidate the signaling pathway involving CREB and TRPC4 channels in response to ATP.
  • To determine the contribution of TRPC4 channels to ATP-induced calcium influx and proliferation.

Main Methods:

  • Human PASMC were treated with low-dose ATP.
  • CREB phosphorylation and TRPC4 protein expression were assessed.
  • TRPC4 expression was manipulated using siRNA.
  • Capacitative calcium entry (CCE) and cell proliferation were measured.

Main Results:

  • Long-term low-dose ATP treatment increased CREB phosphorylation and TRPC4 expression in human PASMC.
  • CREB phosphorylation preceded TRPC4 upregulation, and a CREB mutant abolished this effect.
  • ATP enhanced CCE, which was attenuated by TRPC4 knockdown.
  • TRPC4 knockdown inhibited ATP-induced PASMC proliferation.

Conclusions:

  • Low-dose ATP stimulates human PASMC proliferation through a pathway involving CREB-mediated TRPC4 upregulation.
  • This mechanism enhances TRPC4 channel activity and capacitative calcium entry, contributing to mitogenesis.

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