Receptor-specific crosstalk between prostanoid e receptor 3 and bombesin receptor subtype 3

Abstract

Bombesin receptor subtype 3 (BRS-3) is a GPCR that is expressed in the CNS, peripheral tissues, and tumors.Our understanding of BRS-3's role in physiology and pathophysiology is limited because its natural ligand is unknown. In an attempt to identify this ligand,we screened toad skin (Bufo bufo gargarizans Cantor) extracts and identified prostaglandins as putative ligands. In BRS-3-transfected human embryonic kidney (HEK) cells, we found that prostaglandins,with prostaglandin E2 (PGE2) being themost potent, fulfill the pharmacologic criteria of affinity, selectivity, and specificity to be considered as agonists to the BRS-3 receptor. However, PGE2 is unable to activateBRS-3 in different cellular environments.We speculated thatEP receptorsmight be the cause of this cellular selectivity, and we found that EP3 is the receptor primarily responsible for the differential PGE2 effect. Consequently, we reconstituted the HEK environment in Chinese hamster ovary (CHO) cells and found that BRS-3 and EP3 interact to potentiatePGE2 signaling. This potentiating effect is receptor specific, and it occurs only when BRS-3 is paired to EP3.Our study represents an example of functional crosstalk between two distantly relatedGPCRs and may be of clinical importance forBRS-3-targeted therapies.