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

Abstract

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.

Abstract

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. Messenger RNAs for prostanoid receptors EP1, EP2, EP4, DP2, and TP are expressed in INS‐1 (832/3) cells. PGE ₂ reduces INS‐1 (832/3) glucose‐stimulated insulin secretion (GSIS) specifically through EP3. DP, FP, IP, and TP receptor agonists also reduce GSIS, but not through their targets, only through cross‐reactivity with EP3. Culture conditions mimicking type 2 diabetes induce INS‐1 (832/3) cell PGE ₂ production and defective GSIS that can be partially restored with an EP3 antagonist. EP3 splice variants with constitutive activity may reduce INS‐1 (832/3) cell viability. EP3 is a critical regulator of INS‐1 (832/3) function, and EP3 signalling promotes β‐cell dysfunction in diabetic conditions. Many supposedly selective prostanoid receptor agonists also activate EP3.