PEPTIDE hormones, neurotransmitters, and autacoids activate a family of seven-transmembrane-domain receptors¹. Each of these receptors specifically couples to one of several G proteins, G_s, G_i, G_o and G_p, to activate a specific second messenger system². Cell surface receptors for prostanoids have been characterized pharmacologically³ and the complementary DNAs for thrombox-ane A₂ receptor^4,5 and the EP3 subtype of the prostaglandin (PG)E receptor⁶ reveal that they belong to the seven-transmembrane-domain receptor family. The EP3 receptor mediates the diverse physiological actions of PGE₂ (ref. 3). Although most of them occur through coupling of the EP3 receptor to Gⁱ and inhibition of adenylyl cyclase, the EP3-mediated contraction of uterine muscle can only occur by activation of another second messenger pathway⁷. In chromaffin cells, two different second messenger pathways are activated by PGE2 binding to an apparently single EP3 receptor class₈. Here we show that at least four isoforms of the EP3 receptor, which differ only at their C-terminal tails and are produced by alternative splicing, couple to different G proteins to activate different second messenger systems.