The PGE2–EP receptor axis in urinary tract smooth muscle: one signaling system, three organ-specific strategies

Prostaglandin E2 (PGE2) is the dominant lipid mediator generated within the urinary tract wall, yet the direction of its action reverses from organ to organ: it excites the bladder, suppresses the ureter, and relaxes the prostate and urethra. This review asks why one signaling system produces three opposite outputs and what that organization offers for therapy. Synthesizing 115 publications, from classical organ-bath studies to current clinical trials, we first outline the molecular toolkit—an inducible biosynthetic arm and four EP receptor subtypes with asymmetric G protein coupling—that makes divergent deployment chemically possible. We then assemble the organ-specific evidence. In the bladder, EP1/EP3-driven contraction and afferent sensitization are distributed across a chimera of smooth muscle, urothelium, interstitial cells, and nerves, and are amplified by obstruction, inflammation, denervation, and aging. In the ureter, EP2-mediated inhibition of peristalsis—with the EP4 component still an inference from coupling logic—is the property that NSAIDs, the first-line analgesics for renal colic, act upon, although whether their benefit arises from restoring motility, reducing edema, or dampening nociceptors remains unresolved. In the outflow tract, the weakest-evidenced arm, EP-dependent relaxation is supported by rodent pharmacology and by a single clinical association between pathway activation and BPH that fails medical therapy. Within this PGE2-centered frame, receptor-subtype repurposing across organs is consistent with rules that pathology reweights but does not erase—weights inferred from function rather than measured receptor abundance—and much of the literature’s apparent contradiction dissolves under five methodological variables. We propose the axis as one system deployed in three organ-specific strategies—a testable working hypothesis, with the outflow tract currently a plausible third member, under which choosing a receptor subtype would approximate choosing an organ. The hypothesis maps onto therapy as one established success, two credible prospects—EP2/EP3 agonism for underactive bladder and EP2 agonism for stone expulsion—and one open frontier, and we define the maps, conditional knockouts, verified ligands, and computational tools needed to convert it into organ-directed pharmacology.