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Endocrine Abstracts (2022) 86 P267 | DOI: 10.1530/endoabs.86.P267

SFEBES2022 Poster Presentations Reproductive Endocrinology (36 abstracts)

Spatial and ligand-directed control of Prostaglandin EP2 signalling

Abigail Walker , Holly Parkin , David Woodward & Aylin Hanyaloglu

Imperial College London, London, United Kingdom

Prostaglandin E2 acts via 4 GPCRs, EP1-4. EP2 regulates inflammation and has important roles in cardiovascular function, reproduction, and malignancy. GPCR signalling and trafficking are highly integrated as signals from the endomembrane can exhibit distinct profiles from the plasma membrane. Whether EP2 activity is spatially regulated and if this is modified by ligand bias is currently unknown. In HEK 293 cells, three selective EP2 ligands, butaprost, AH13205, and PGN9856i, elicited potent cAMP responses, with EC50s of 415 nM, 436 nM and 2.59 nM, respectively. In both HEK 293 cells and primary myometrial cells from term pregnancies only AH13205 and butaprost were able to increase intracellular Ca2+ levels or PGE2 secretion, and AH13205 increased PGE2 secretion ~40 fold more than butaprost. In HEK 293 cells whilst EP2 exhibited minimal ligand-induced internalisation with all ligands, there was significant constitutive internalisation, which was dynamin-dependent. The dynamin inhibitor Dyngo-4a also reduced cAMP signalling by 70% and the maximal Ca2+ response by 50%. Neither butaprost nor AH13205-dependent PGE2 release was dynamin-dependent, demonstrating a differential spatial requirement for EP2 signalling. Overall, EP2 is constitutively internalised and undergoes minimal ligand-induced internalisation. However, there is a differential spatial requirement for cAMP, Ca2+ and PGE2 signalling in HEK 293 cells demonstrating the physiological importance of constitutive EP2 trafficking. Furthermore, there is distinct ligand bias as different ligands exhibit either extreme inflammatory bias via the Gαq-Ca2+-PGE2 pathway or bias to the Gαs-cAMP pathway. These ligands provide novel tools for probing EP2 function and may provide a novel therapeutic strategy for maintenance of pregnancy where it is beneficial to promote the Gas-cAMP pathway without promoting inflammation.

Volume 86

Society for Endocrinology BES 2022

Harrogate, United Kingdom
14 Nov 2022 - 16 Nov 2022

Society for Endocrinology 

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