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The first cloning of the mammalian GnRH receptor was accomplished by Tsutsumi et al.,[138] who used RNA from the αT3 mouse gonadotrope cell line. Subsequently, a large number of GnRH receptors have been cloned from many species in all the major vertebrate classes, as well as from modern representatives of protochordate progenitors of the vertebrates.[66] Although only one functional type of GnRH receptor and two endogenous ligands (GnRH I and GnRH II) exist in humans, coexistence of two or three types of GnRH ligands and receptors was identified in the majority of chordate and vertebrate species.[66] However, the type II GnRH receptor has been silenced by stop codons and frameshift deletions in certain mammals, including human, chimpanzee, rat, mouse, cow, and sheep.[139]

The GnRH receptors are classical G protein–coupled receptors (GPCRs) with seven transmembrane domains (TMs) connected by extracellular loops (ECLs) and intracellular loops (ICLs) …