Receptor‐specific crosstalk between prostanoid E receptor 3 and bombesin receptor subtype 3

What is it about?

This study is of broad interest to the field of cell signaling. It deals with a much-sought after orphan GPCR for which we do not have an endogenous ligand but which, in spite of this lack, was the target of a drug discovery program which reached phase 2. Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor that belongs to the bombesin receptor family. Because mice lacking BRS-3 display late onset obesity it has been the target of many deorphanization attempts. In this manuscript we chose to screen toad skin extracts, the source of bombesin, and identified prostaglandins as putative ligands. We show that prostaglandins, PGE2 being the most potent, fulfill the pharmacological criteria of affinity, selectivity and specificity to be considered as agonists to the BRS-3 receptor when transfected in HEK cells. However, we also found that PGE2 was unable to activate BRS-3 in different cellular environments (CHO and Hela cells). We suspected that endogenous prostanoid receptors, in particular EP3, may be the cause of this cellular selectivity. Consequently, we set up to reconstitute the HEK environment in CHO cells and found that BRS-3 and EP3 interact to potentiate PGE2 signaling. This potentiating effect is receptor specific and occurs only when BRS-3 is paired to EP3 receptor. This represents a surprising example of functional cross-talk between two distantly related GPCRs and is of great interest to cell signaling studies. Our study may be of clinical importance for BRS-3 targeted therapies.

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