A novel biased allosteric compound inhibitor of parturition selectively impedes the prostaglandin F2alpha-mediated Rho/ROCK signaling pathway.
The prostaglandin F2alpha (PGF2alpha) 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 NH(2)-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 PGF2alpha- and lipopolysaccharide-induced preterm labor. PDC113.824 inhibited PGF2alpha-mediated, G(alpha)(12)-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 PGF2alpha binding. In contrast to its negative allosteric modulating effects on Rho/ROCK signaling, PDC113.824 acted as a positive allosteric modulator on PGF2alpha-mediated protein kinase C and ERK1/2 signaling. This bias in receptor-dependent signaling was explained by an increase in FP receptor coupling to G(alpha)(q), at the expense of coupling to G(alpha)(12). 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.
Goupil
Eugénie
E
Department of Medicine, McGill University Health Center Research Institute, Montréal H3A 1A1, Canada.
Tassy
Danaë
D
Bourguet
Carine
C
Quiniou
Christiane
C
Wisehart
Veronica
V
Pétrin
Darlaine
D
Le Gouill
Christian
C
Devost
Dominic
D
Zingg
Hans H
HH
Bouvier
Michel
M
Saragovi
Horacio Uri
HU
Chemtob
Sylvain
S
Lubell
William D
WD
Claing
Audrey
A
Hébert
Terence E
TE
Laporte
Stéphane A
SA
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D015237:Dinoprost / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000188:drug therapy; D036801:Parturition / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism*
D010455:Peptides; D015237:Dinoprost; D054460:rho-Associated Kinases; D011493:Protein Kinase C