Genetic and pharmacological analysis of prostanoid receptor function

Abstract

Prostaglandins and their precursors Membrane prostanoid receptors: studies in knockout miceEight types and subtypes of membrane prostanoid receptors are conserved in mammals from mouse to human (2): the PGD receptor (DP), four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4), the PGF receptor (FP), the PGI receptor (IP), and the TxA receptor (TP).All are G protein-coupled rhodopsin-type receptors with seven transmembrane domains, and each is encoded by different genes.In addition, there are several splice variants of the EP3, FP, and TP receptors, which differ only in their C-terminal tails.Among the eight types and subtypes, the IP, DP, EP2, and EP4 receptors mediate a cAMP rise and have been termed "relaxant" receptors, whereas the TP, FP, and EP1 receptors induce calcium mobilization and constitute a "contractile" receptor group.The remaining receptor, EP3, induces a decline in cAMP levels and has been termed the "inhibitory" receptor.However, the effects of prostanoids on these G protein-coupled signaling pathways may change as a function of ligand concentration or structure.Thus, while PGI 2 analogs ligate the IP and activate adenylate cyclase via G s in a dosedependent manner, higher concentrations of the ligand couple the IP to phospholipase C activation and calcium mobilization (3), probably via G q .Similarly, activation of the FP in cardiomyocytes by either PGF 2α , its cognate ligand, or 8,12-iso-iPF 2α -III, a PGF 2α isomeric