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Prostacyclin receptor-mediated activation of extracellular signal-regulated kinases 1 and 2

Kit Man Chu1, Kevin B S Chow, Yung H Wong

  • 1Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong S.A.R, China.

Cellular Signalling
|January 8, 2004
PubMed

Insights

The prostacyclin mimetic cicaprost activates extracellular signal-regulated kinases 1 and 2 (ERK1/2) in cells with prostacyclin receptors. This activation involves protein kinase C and phosphoinositide 3-kinase, independent of cyclic AMP.

Area of Science:

  • Cellular signaling pathways
  • Molecular pharmacology
  • Receptor-mediated signal transduction

Background:

  • Prostacyclin receptors (IP receptors) mediate cellular responses to prostacyclin and its analogs.
  • Extracellular signal-regulated kinases (ERK1/2) are key components of intracellular signaling cascades.
  • Understanding IP receptor signaling is crucial for developing targeted therapeutics.

Purpose of the Study:

  • To investigate the signaling mechanisms by which cicaprost activates ERK1/2 in cells expressing prostacyclin receptors.
  • To determine the role of cyclic AMP (cAMP) and other signaling pathways in this activation.
  • To compare signaling in cells with transiently expressed versus endogenously expressed IP receptors.

Main Methods:

  • Transiently transfecting Chinese hamster ovary (CHO) cells with human (hIP-CHO) or mouse (mIP-CHO) prostacyclin receptors.
  • Treating cells with cicaprost and measuring ERK1/2 phosphorylation.
  • Utilizing protein kinase C inhibitors and agents that modulate cyclic AMP levels.
  • Assessing the correlation between ERK1/2 activity and cyclic AMP production.

Main Results:

  • Cicaprost increased ERK1/2 phosphorylation in hIP-CHO and mIP-CHO cells (EC50 values 60 and 83 nM, respectively).
  • This activation was inhibited by protein kinase C inhibitors and agents that elevate cyclic AMP.
  • A weak correlation was observed between ERK1/2 activity and cyclic AMP modulation.
  • 3-isobutyl-1-methylxanthine inhibited cicaprost-stimulated phospho-ERK1/2, suggesting phosphoinositide 3-kinase involvement.

Conclusions:

  • IP receptor-mediated ERK1/2 activation in CHO cells is dependent on Gq/11 and protein kinase C.
  • Phosphoinositide 3-kinase plays a role in this signaling pathway.
  • The activation of ERK1/2 by IP receptors in this context is insensitive to cyclic AMP levels generated by the receptor.

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