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Expression, Structure, Function, and Evolution of Gonadotropin-Releasing Hormone (GnRH) Receptors GnRH-R1^SHS and GnRH-R2^PEY in the Teleost, Astatotilapia burtoni

University of Cape Town/Medical Research Council Research Group for Receptor Biology, Institute of Infectious Diseases and Molecular Medicine and Division of Medical Biochemistry (C.A.F., M.C., S.M.), and Department of Medicine (C.A.F.), University of Cape Town Faculty of Health Sciences, Observatory 7925, South Africa; Department of Biological Sciences and Program in Neuroscience (C.-C.C., L.G., R.D.F.), Stanford University, Stanford, California 94305; Department of Molecular Biology and Genetics (K.E.W.), Cornell University, Ithaca, New York 14853; and Department of Molecular and Cell Biology (N.B., N.I.), University of Cape Town, Rondebosch 7700, South Africa

Address all correspondence and requests for reprints to: R. D. Fernald, Department of Biological Sciences and Program in Neuroscience, Stanford University, Stanford, California 94305-2130. E-mail: rfernald{at}stanford.edu.

Multiple GnRH receptors are known to exist in nonmammalian species, but it is uncertain which receptor type regulates reproduction via the hypothalamic-pituitary-gonadal axis. The teleost fish, Astatotilapia burtoni, is useful for identifying the GnRH receptor responsible for reproduction, because only territorial males reproduce. We have cloned a second GnRH receptor in A. burtoni, GnRH-R1^SHS (SHS is a peptide motif in extracellular loop 3), which is up-regulated in pituitaries of territorial males. We have shown that GnRH-R1^SHS is expressed in many tissues and specifically colocalizes with LH in the pituitary. In A. burtoni brain, mRNA levels of both GnRH-R1^SHS and a previously identified receptor, GnRH-R2^PEY, are highly correlated with mRNA levels of all three GnRH ligands. Despite its likely role in reproduction, we found that GnRH-R1^SHS has the highest affinity for GnRH2 in vitro and low responsivity to GnRH1. Our phylogenetic analysis shows that GnRH-R1^SHS is less closely related to mammalian reproductive GnRH receptors than GnRH-R2^PEY. We correlated vertebrate GnRH receptor amino acid sequences with receptor function and tissue distribution in many species and found that GnRH receptor sequences predict ligand responsiveness but not colocalization with pituitary gonadotropes. Based on sequence analysis, tissue localization, and physiological response we propose that the GnRH-R1^SHS receptor controls reproduction in teleosts, including A. burtoni. We propose a GnRH receptor classification based on gene sequence that correlates with ligand selectivity but not with reproductive control. Our results suggest that different duplicated GnRH receptor genes have been selected to regulate reproduction in different vertebrate lineages.