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Volume 272, Number 43, Issue of October 24, 1997 pp. 27147-27154
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional Characterization of the Ocular Prostaglandin F₂ (PGF₂) Receptor
ACTIVATION BY THE ISOPROSTANE, 12-iso-PGF₂

(Received for publication, June 2, 1997)

Priya Kunapuli , John A. Lawson , Joshua Rokach ^§ and Garret A. FitzGerald

From the  Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the ^§ Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901

Prostaglandin F₂ (PGF₂) is a product of cyclooxygenase-catalyzed metabolism of arachidonic acid. Recently, PGF₂ analogs have been hypothesized to reduce intraocular pressure via relaxation of the ciliary muscle. To investigate the molecular basis of PGF₂ receptor (FP) activation in the eye, we cloned the FP from a human ciliary body (hcb) cDNA library. The open reading frame of the hcb-FP cDNA was identical to the uterine FP cDNA. The hcb-FP appeared to be predominantly membrane-localized, as visualized by an FP-specific peptide antibody, and coupled to inositol phosphate formation when stably expressed in HEK 293 cells. Interestingly, the hcb-FP could also be activated by the F₂ isoprostane, 12-iso-PGF₂, in addition to its cognate ligand, PGF₂. 12-iso-PGF₂ was less potent (EC₅₀ = 5 µM) than PGF₂ (EC₅₀ = 10 nM) in generating inositol phosphates via the hcb-FP in HEK 293 cells. Both ligands also stimulated mitogenesis in NIH 3T3 cells. Although 12-iso-PGF₂ caused a dose-dependent activation of the FP, it failed to activate the recombinant human prostacyclin receptor and caused only minimal activation of the thromboxane receptor isoforms stably expressed in HEK 293 cells. Four additional F₂ isoprostanes, 8-iso-PGF₂, IPF₂-I, IPF₂-III, and 9,11-PGF₂, caused trivial, or no, activation of the FP. Consistent with these observations, only PGF₂ and 12-iso-PGF₂ caused rapid homologous desensitization of FP and also exhibited cross-desensitization, with PGF₂ resulting in a maximum of ~60% desensitization. The human FP may thus be activated specifically, by the free radical-catalyzed F₂ isoprostane, 12-iso-PGF₂, in addition to the cyclooxygenase product, PGF₂. Incidental receptor activation by isoprostanes may complement the actions of PGF₂ in clinical syndromes where oxidant stress and augmented prostaglandin biosynthesis coincide.

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