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Position of Pro and Ser near Glu^7.32 in the Extracellular Loop 3 of Mammalian and Nonmammalian Gonadotropin-Releasing Hormone (GnRH) Receptors Is a Critical Determinant for Differential Ligand Selectivity for Mammalian GnRH and Chicken GnRH-II

Hormone Research Center (C.W., O.Y., K.M., D.Y.O., J.Y.S., H.B.K.), Chonnam National University, Gwangju 500-757, Republic of Korea; Department of Molecular Cell Biology (K.K.K.), Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea; Korea Chemical Bank (C.H.C.), Korea Research Institute of Chemical Technology, Daejeon 305-606, Republic of Korea; and Department of Chemistry (C.J.L.), Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea

Address all correspondence and requests for reprints to: Jae Young Seong, Ph.D., Hormone Research Center, Chonnam National University, Gwangju 500-757, Republic of Korea. E-mail: jyseong{at}chonnam.ac.kr.

A Glu/Asp^7.32 residue in the extracellular loop 3 of the mammalian GnRH receptor (GnRHR) is known to interact with Arg⁸ of mammalian GnRH (mGnRH), which may confer preferential ligand selectivity for mGnRH than for chicken GnRH-II (cGnRH-II). However, some nonmammalian GnRHRs also have the Glu/Asp residue at the same position, yet respond better to cGnRH-II than mGnRH. Amino acids flanking Glu/Asp^7.32 are differentially arranged such that mammalian and nonmammalian GnRHRs have an S-E/D-P motif and P-X-S/Y motif, respectively. We presumed the position of Ser^7.31 or Pro^7.33 of rat GnRHR as a potential determinant for ligand selectivity. Either placing Pro before Glu^7.32 or placing Ser after Glu^7.32 significantly decreased the sensitivity and/or efficacy for mGnRH, but slightly increased that for cGnRH-II in several mutant receptors. Among them, those with a PEV, PES, or SES motif exhibited a marked decrease in sensitivity for mGnRH such that cGnRH-II had a higher potency than mGnRH, showing a reversed preferential ligand selectivity. Chimeric mGnRHs in which positions 5, 7, and/or 8 were replaced by those of cGnRH-II revealed a greater ability to activate these mutant receptors than mGnRH, whereas they were less potent to activate wild-type rat GnRHR than mGnRH. Interestingly, a mutant bullfrog type I receptor with the SEP motif exhibited an increased sensitivity for mGnRH but a decreased sensitivity for cGnRH-II. These results indicate that the position of Pro and Ser near Glu^7.32 in the extracellular loop 3 is critical for the differential ligand selectivity between mammalian and nonmammalian GnRHRs.

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