EP3 prostanoid receptor isoforms utilize distinct mechanisms to regulate ERK 1/2 activation

Davelene D. Israel, John W. Regan

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Prostaglandin-E2 (PGE2) is a hormone derived from the metabolism of arachidonic acid whose functions include regulation of platelet aggregation, fever and smooth muscle contraction/relaxation. PGE2 mediates its physiological and pathophysiological effects through its binding to four G-protein coupled receptor subtypes, named EP1, EP2, EP3 and EP4. The EP3 prostanoid receptor is unique in that it has multiple isoforms generated by alternative mRNA splicing. These splice variants display differences in tissue expression, constitutive activity and regulation of signaling molecules. To date there are few reports identifying differential activities of EP3 receptor isoforms and their effects on gene regulation. We generated HEK cell lines expressing the human EP3-Ia, EP3-II or EP3-III isoforms. Using immunoblot analysis we found that nM concentrations of PGE2 strongly stimulated the phosphorylation of ERK 1/2 by the EP3-II and EP3-III isoforms; whereas, ERK 1/2 phosphorylation by the EP3-Ia isoform was minimal and only occurred at μM concentrations of PGE2. Furthermore, the mechanisms of the PGE2 mediated phosphorylation of ERK 1/2 by the EP3-II and EP3-III isoforms were different. Thus, PGE2 stimulation of ERK 1/2 phosphorylation by the EP3-III isoform involves activation of a Gαi/PI3K/PKC/Src and EGFR-dependent pathway; while for the EP3-II isoform it involves activation of a Gαi/Src and EGFR-dependent pathway. These differences result in unique differences in the regulation of reporter plasmid activity for the downstream effectors ELK1 and AP-1 by the EP3-II and EP3-III prostanoid receptor isoforms.

Original languageEnglish (US)
Pages (from-to)238-245
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Issue number4
StatePublished - Apr 2009


  • E Prostanoid receptor
  • ERK 1/2
  • Epidermal growth factor receptor
  • Phosphoinositide-3 kinase
  • Prostaglandin E
  • Protein kinase C

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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