The prostacyclin receptor (IP), a G protein-coupled receptor, mediates the actions of the prostanoid prostacyclin and its mimetics. IPs from a number of species each contain identically conserved putative isoprenylation CAAX motifs, each with the sequence CSLC. Prostacyclin (prostaglandin (PG)1 I 2 ) is a labile metabolite of arachidonic acid, which is synthesized by the sequential actions of PGH 2 endoperoxide synthases 1 and 2 and prostacyclin synthase (1). The actions of prostacyclin generally counteract those of thromboxane A 2 , and thus the relative level of these two prostanoids in the circulation are important in the local control of vascular tone and platelet aggregation (2, 3). The main physiologic roles of thromboxane A 2 and prostacyclin are their contribution to the maintenance of vascular hemostasis: thromboxane A 2 , synthesized primarily by platelets, induces platelet shape change and aggregation and constriction of bronchial and vascular smooth muscle, whereas prostacyclin, mainly synthesized by the vascular endothelium, is a potent inhibitor of platelet aggregation and induces vasodilation (4 -7). Moreover, prostacyclin has been reported to confer a cytoprotective effect against tissue injury in acute myocardial ischemia or following hypoxic exposure of vascular endothelial cells (8). Imbalances in thromboxane A 2 or prostacyclin have been reported to be a major contributing factor in the development of a number of cardiovascular disorders including thrombosis, myocardial infarction, unstable angina, stroke, and atherosclerosis (9 -13). In addition to its central role in the cardiovascular system, prostacyclin may be important in the regulation of renal blood flow (14); it also acts as a negative feedback regulator of histamine secretion from mast cells (15) and acts as a lipolytic agent, antagonizing the antilipolytic effect of PGE 2 , in adipocytes (16).The actions of prostacyclin are mediated via interaction with a specific cell surface receptor, termed the prostacyclin receptor or IP (17). The major intracellular signaling pathway used is stimulation of adenylyl cyclase leading to increases in intracellular cAMP (18,19), a pathway thought to be relevant to inhibition of platelet aggregation and vascular smooth muscle relaxation (3). However, recent evidence indicates that IP agonists may couple to multiple signaling pathways including activation and inhibition of adenylyl cyclase, via G s and G i , respectively, stimulation of phosphoinositide metabolism, and changes in [Ca 2ϩ ] i concentrations (20,21). Evidence also exists to indicate that iloprost, a stable carbacyclin analogue of prostacyclin, can stimulate opening of ATP sensitive K ϩ channels resulting in hyperpolarization and relaxation of canine carotid artery (22).Molecular cloning of the human (23, 24), mouse (25), and rat