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Molecular Pharmacology

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Research ArticleArticle

A Single Amino-Acid Substitution in the EP2Prostaglandin Receptor Confers Responsiveness to Prostacyclin Analogs

Karen M. Kedzie, John E. Donello, Heather A. Krauss, John W. Regan and Daniel W. Gil
Molecular Pharmacology September 1998, 54 (3) 584-590; DOI: https://doi.org/10.1124/mol.54.3.584
Karen M. Kedzie
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John E. Donello
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Heather A. Krauss
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John W. Regan
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Daniel W. Gil
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Abstract

A high degree of homology between the four Gs-coupled prostaglandin (PG) receptors [EP2, EP4, prostacyclin (IP), PGD2 (DP)] and the four Gq/Gi-coupled receptors [EP1, EP3, PGF2α (FP), thromboxane A2(TP)] suggests that prostaglandin receptors evolved functionally from an ancestral EP receptor before the development of distinct binding epitopes. If so, ligand selectivity should be determined by a limited number of amino acids. EP2 receptor transmembrane domain residues that are similar to those in the EP4 receptor but differ from those in the IP receptor were mutated to the corresponding IP receptor residue. Activation of the mutant receptors by PGE2 (EP2 ligand), iloprost (stable prostacyclin analog), and PGE1 (EP2/IP ligand) was determined using a cAMP-dependent reporter gene assay. A Leu304-to-tyrosine substitution in the seventh transmembrane domain enhanced iloprost potency approximately 100-fold. A glycine substitution at Ser120 in the third transmembrane domain had no effect on drug potency but improved the response of the Tyr304 mutant. The potency of the natural prostaglandins PGF2α and PGD2 was not enhanced by the mutations. In contrast, the potency of all prostaglandins was reduced 10- to 100-fold when arginine 302, which is thought to be a counterion for the prostaglandin carboxylic acid, was mutated. Thus, a single amino acid change resulted in a selective gain of function for iloprost, which is consistent with the proposed phylogeny of the prostaglandin receptors.

Footnotes

    • Received January 15, 1998.
    • Accepted June 5, 1998.
  • Send reprint requests to: Dr. Daniel W. Gil, Biological Sciences, RD-2C, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612. E-mail: gil_daniel{at}allergan.com

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (3)
Molecular Pharmacology
Vol. 54, Issue 3
1 Sep 1998
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Research ArticleArticle

A Single Amino-Acid Substitution in the EP2Prostaglandin Receptor Confers Responsiveness to Prostacyclin Analogs

Karen M. Kedzie, John E. Donello, Heather A. Krauss, John W. Regan and Daniel W. Gil
Molecular Pharmacology September 1, 1998, 54 (3) 584-590; DOI: https://doi.org/10.1124/mol.54.3.584

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Research ArticleArticle

A Single Amino-Acid Substitution in the EP2Prostaglandin Receptor Confers Responsiveness to Prostacyclin Analogs

Karen M. Kedzie, John E. Donello, Heather A. Krauss, John W. Regan and Daniel W. Gil
Molecular Pharmacology September 1, 1998, 54 (3) 584-590; DOI: https://doi.org/10.1124/mol.54.3.584
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