Rat prostaglandin EP3 receptor is highly promiscuous and is the sole prostanoid receptor family member that regulates INS-1 (832/3) cell glucose-stimulated insulin secretion.

Chronic elevations in fatty acid metabolites termed prostaglandins can be found in circulation and in pancreatic islets from mice or humans with diabetes and have been suggested as contributing to the β-cell dysfunction of the disease. Two-series prostaglandins bind to a family of G-protein-coupled receptors, each with different biochemical and pharmacological properties. Prostaglandin E receptor (EP) subfamily agonists and antagonists have been shown to influence β-cell insulin secretion, replication, and/or survival. Here, we define EP3 as the sole prostanoid receptor family member expressed in a rat β-cell-derived line that regulates glucose-stimulated insulin secretion. Several other agonists classically understood as selective for other prostanoid receptor family members also reduce glucose-stimulated insulin secretion, but these effects are only observed at relatively high concentrations, and, using a well-characterized EP3-specific antagonist, are mediated solely by cross-reactivity with rat EP3. Our findings confirm the critical role of EP3 in regulating β-cell function, but are also of general interest, as many agonists supposedly selective for other prostanoid receptor family members are also full and efficacious agonists of EP3. Therefore, care must be taken when interpreting experimental results from cells or cell lines that also express EP3.