A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway*

  1. Stéphane A. Laporte‡§,5
  1. From the ‡Department of Medicine, McGill University Health Center Research Institute, Montréal H3A 1A1,
  2. the §Department of Pharmacology and Therapeutics, McGill University, Montréal H3G 1Y6,
  3. the Departments of Pharmacology,
  4. ‖Chemistry, and
  5. ‡‡Biochemistry, Université de Montréal, Montréal H3C 3J7, and
  6. the **Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal H3T 1C5, Canada
  1. 4 A Chercheur National of the “Fonds de la Recherche en Santé du Québec.” To whom correspondence may be addressed. E-mail: terence.hebert{at}mcgill.ca.
  2. 5 A Canada Research Chair in Molecular Endocrinology. To whom correspondence may be addressed. E-mail: stephane.laporte{at}mcgill.ca.

Abstract

The prostaglandin F2α (PGF2α) receptor (FP) is a key regulator of parturition and a target for pharmacological management of preterm labor. However, an incomplete understanding of signaling pathways regulating myometrial contraction hinders the development of improved therapeutics. Here we used a peptidomimetic inhibitor of parturition in mice, PDC113.824, whose structure was based on the NH2-terminal region of the second extracellular loop of FP receptor, to gain mechanistic insight underlying FP receptor-mediated cell responses in the context of parturition. We show that PDC113.824 not only delayed normal parturition in mice but also that it inhibited both PGF2α- and lipopolysaccharide-induced preterm labor. PDC113.824 inhibited PGF2α-mediated, Gα12-dependent activation of the Rho/ROCK signaling pathways, actin remodeling, and contraction of human myometrial cells likely by acting as a non-competitive, allosteric modulator of PGF2α binding. In contrast to its negative allosteric modulating effects on Rho/ROCK signaling, PDC113.824 acted as a positive allosteric modulator on PGF2α-mediated protein kinase C and ERK1/2 signaling. This bias in receptor-dependent signaling was explained by an increase in FP receptor coupling to Gαq, at the expense of coupling to Gα12. Our findings regarding the allosteric and biased nature of PDC113.824 offer new mechanistic insights into FP receptor signaling relevant to parturition and suggest novel therapeutic opportunities for the development of new tocolytic drugs.

Footnotes

  • ↵1 A Canada Research Chair in Signal Transduction and Molecular Pharmacology.

  • ↵2 These two authors are inventors on a patent application for PDC113.824, which is licensed to PDC Biotech. The other authors declare no conflict of interest.

  • ↵3 Recipient of a New Investigator Award from the CIHR.

  • ↵* This work was supported by a Canadian Institutes of Health (CIHR) Research Team Grant in GPCR Allosteric Regulation (CTiGAR, CTP 79848, to H. U. S., W. D. L., S. C., A. C., T. E. H., S. A. L., and M. B.) and CIHR Grants MOP-36279 (to T. E. H.) and PRG-82673 and MOP-74603 (to S. A. L.).

  • ↵Graphic The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and text.

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  1. First Published on June 15, 2010 doi: 10.1074/jbc.M110.115196 The Journal of Biological Chemistry 285, 25624-25636.
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