Functional domains essential for Gs activity in prostaglandin EP2 and EP3 receptors

Yukihiko Sugimoto, Toshiyuki Nakato, Ayumi Kita, Noriyuki Hatae, Hiroyuki Tabata, Satoshi Tanaka, Atsushi Ichikawa

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The interaction of cell surface hormone receptors with heterotrimeric G proteins is crucial for hormonal actions. The domains of the receptor, which interact with and activate G protein, have been extensively studied. However, precise molecular mechanisms underlying regulation of the receptor-induced G protein activation are still poorly understood. Prostaglandin E2 (PGE2) receptors comprise of four subtypes, EP1, EP2, EP3 and EP4. Among them, EP2 and EP4 couple to Gs and EP3 to Gi. To assess the functional domains essential for Gs activation in prostanoid receptors, EP2, EP3β and each intracellular loop- (IC-) interchanged EP2/EP3 chimeras were tested for agonist binding and functional responses. In EP2 receptor, substitution of IC1 or IC3 resulted in loss of binding activity, while substitution of IC2, N- (IC2N) or C-terminal half region of IC2 (IC2C) had no effects on the binding activity. Wild-type EP2 and IC2C-substituted EP2 showed agonist-induced Gs activity, but IC2- and IC2N-substituted EP2 failed to elicit Gs activity upon agonist stimulation. On the other hand, in EP3 receptor substitution of IC1 resulted in loss of PGE2 binding, while substitution of IC2, IC3, IC2N or IC2C had no effects on binding activity. Wild-type EP3β, IC3- or IC2C-substituted EP3 failed to show Gs activity upon agonist stimulation, but IC2- or IC2N-substituted EP3 chimera showed agonist-dependent Gs activity. These results indicated that the second intracellular loop of the EP2 plays an essential role in activation of Gs.

Original languageEnglish
Pages (from-to)135-141
Number of pages7
JournalLife Sciences
Volume74
Issue number2-3
DOIs
Publication statusPublished - Dec 5 2003

Keywords

  • G protein
  • PGE
  • Prostaglandin E subtypes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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    Sugimoto, Y., Nakato, T., Kita, A., Hatae, N., Tabata, H., Tanaka, S., & Ichikawa, A. (2003). Functional domains essential for Gs activity in prostaglandin EP2 and EP3 receptors. Life Sciences, 74(2-3), 135-141. https://doi.org/10.1016/j.lfs.2003.09.002