Differences in structure—function relations between nonmammalian and mammalian GnRH receptors: what we have learnt from the African catfish GnRH receptor

Abstract

Mammalian gonadotropin-releasing hormone (GnRH) receptors differ from other G-protein coupled receptors (GPCRs) in lacking the intracellular C-terminal tail and in showing an exchange of two otherwise highly conserved aspartate protease (Asp) and asparaginyl (Asn) residues in TM 2 and 7, respectively. However, the first GnRH receptor characterized from a nonmammalian vertebrate, the African catfish, contains an intracellular C-terminal tail and has Asp residues. Next to structural variations, differences between mammalian and nonmammalian GnRH receptors are found in their pharmacology and their regulation. In addition, the results of studies on catfish and mammalian GnRH receptor expression, regulation and activation, and ligand binding are summarized. To this end, mammalian-nonmammalian chimeric GnRH receptors, site-directed mutagenesis of GnRH receptors, various GnRH analogs, and a three-dimensional model of the receptor-ligand complex were used. It is demonstrated that the catfish GnRH receptor is susceptible to agonist-induced phosphorylation and that Ser in the C terminal tail is the major phospho-acceptor site in this process. Mammalian GnRH receptors, on the contrary, are resistant to agonist-dependent phosphorylation due to the lack of a C-terminal tail.