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Multiple Signal Transduction Pathways through Two Prostaglandin E Receptor EP₃ Subtype Isoforms Expressed in Human Uterus

Departments of Medicine and Clinical Science (M.K., I.T., Y.O., T.S., S.M., Y.Ya., A.S., Y.Yo., K.N.), Gynecology and Obstetrics (T.M., N.S.), and Pharmacology (S.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan

Address all correspondence and requests for reprints to: Issei Tanaka, M.D., Ph.D., Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: isseitnk{at}cam.hi-ho.ne.jp

PGE₂ is known to induce uterine contraction by increasing intracellular Ca²⁺. In the present study, to investigate other functions of PGE₂ in human uterus, two EP₃ isoforms were isolated by the RT-PCR method using human uterus polyadenylated ribonucleic acid (RNA). These EP₃ isoforms, named EP_3-V and EP_3-VI, are composed of 402 and 393 amino acid residues, respectively, which are unique compared with EP₃ isoforms of other species. Their N-terminal 359 amino acid residues are identical to those of previously reported human EP₃ isoforms, whereas the two isoforms contained a novel amino acid sequence in their C-terminal tails. The dissociation constant values of EP_3-V and EP_3-VI for PGE₂ were 3.9 and 1.4 nmol/L, respectively, which were consistent with those of previously reported EP₃ isoforms. Signaling experiments revealed that M&B28767, an EP₃ agonist, not only inhibited forskolin-induced cAMP concentrations, but also activated mitogen-activated protein kinase in Chinese hamster ovary cells stably expressing EP_3-V and EP_3-VI. These responses were abolished by treatment with pertussis toxin. In addition, M&B28767 increased cAMP concentrations in EP_3-VI-expressing cells, whereas it did not in EP_3-V-expressing cells. M&B28767 did not stimulate phosphoinositide turnover in EP_3-V- or EP_3-VI-expressing cells. EP_3-V and EP_3-VI messenger RNAs (mRNAs) were detected abundantly in human uterus, whereas weak, but substantial, bands were detected in the lung and kidney in RT-PCR specific for each mRNA. In situ hybridization revealed EP_3-V and EP_3-VI mRNAs in the human myometrium, but not in the endometrium. The present study suggests that EP_3-V and EP_3-VI are possibly involved in the proliferation of cells in human myometrium.

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