SELECTIVE COUPLING OF PROSTAGLANDIN-E RECEPTOR EP3D TO MULTIPLE G-PROTEINS DEPENDING ON INTERACTION OF THE CARBOXYLIC-ACID OF AGONIST AND ARGININE RESIDUE OF 7TH TRANSMEMBRANE DOMAIN

Prostaglandin E receptor EP3D is coupled to stimulation and inhibition of adenylate cyclase and stimulation of phosphatidylinositol turnover . To examine the roles of the interaction of the carboxylic acid of an agonist and its putative binding site, the arginine residue in the se venth transmembrane domain of EP3D, in receptor-G protein coupling, we have mutated the arginine to the non-charged glutamine. TEI-3356, an EP3 agonist with a negatively charged the carboxylic acid, and TEI-434 3, a non-charged methylester of TEI-3356, inhibited the forskolin-stim ulated cAMP formation in the same concentration-dependent manner, but stimulation of basal cAMP formation and Ca2+ mobilization by TEI-4343 was much lower than that by TEI-3356. In the mutant receptor, both TEI -3356 and TEI-4343 showed the inhibition of forskolin-stimulated cAMP formation in the same profile, but did not stimulate basal cAMP format ion or Ca2+ mobilization. These findings suggest that the interaction between the carboxylic acid of agonist and the arginine residue is imp ortant in signal transduction for adenylate cyclase stimulation and Ca 2+ mobilization but not for adenylate cyclase inhibition. (C) 1995 Aca demic Press, Inc.