Programming Prostaglandin EP2 Receptor Activity in Human Labor Via G Protein-Coupled Receptor (GPCR) Crosstalk

Presentation Number: SUN 271
Date of Presentation: April 2nd, 2017

Aylin Hanyaloglu*1, Camilla Larsen2, Shirin Khanjani2, Abigail Walker2, Vasso Terzidou2 and Phillip Bennett1
1Imperial College London, London, United Kingdom, 2Imperial College London

Abstract

Preterm labor, leading to birth, is the major cause of infant death and handicap, thus there is a demand for effective tocolytic drugs to delay preterm birth. However, recent evidence suggests current tocolytics that inhibit contractions but not inflammation may worsen neonatal outcome. Prostaglandins and oxytocin play central roles in the biochemistry of term/pre-term labor. Our recent studies demonstrate that prostaglandin E2 (PGE2) and oxytocin (OT) induce complex signalling responses from their G protein-coupled receptors (GPCRs) that critically mediate both inflammation and contractility, and therefore represent targets for an effective clinical tocolytic strategy. However, to design such an approach requires a more detailed understanding of the specific mechanisms mediating the communication networks between these receptors. Term pregnant human myocytes were extracted from tissue collected either before or after the onset of labor (induced and spontaneous). The PGE2 receptor EP2 activates contrasting relaxatory/anti-labor and pro-inflammatory/pro-labor pathways at term via distinct G proteins (Galphas and Galphaq/11 respectively). Following the onset of labor, EP2 activity is reprogrammed to primarily activate inflammation via signal crosstalk with OT/OT receptor (OTR), by inhibiting EP2-dependent-cAMP signalling and increasing the levels of pro-inflammatory mediators. Interestingly, OT/OTR positively modulates EP2-mediated inflammation by altering its G protein-coupling complement. Use of BRET and proximity ligation assays demonstrate exogenous and endogenous OTR and EP2 form heteromers in term pregnant myometrium. Overall this study demonstrates that EP2 and OTR are programmed during human parturition to differentially regulate pro- and anti-labor responses via GPCR crosstalk, and that these receptor heteromers could represent promising novel tocolytic targets.

 

Disclosure: PB: , ObsEva. Nothing to Disclose: AH, CL, SK, AW, VT