Gonadotropin-releasing hormone 2 suppresses food intake in the zebrafish, Danio rerio

GnRH and its analogs are used extensively for the treatment of hormone-dependent diseases and assisted reproductive techniques. They also have potential as novel contraceptives in men and women. A thorough delineation of the molecular mechanisms involved in ligand binding, receptor activation, and intracellular signal transduction is kernel to understanding disease processes and the development of specific interventions. Twenty-three structural variants of GnRH have been identified in protochordates and vertebrates. In many vertebrates, three GnRHs and three cognate receptors have been identified with distinct distributions and functions. In man, the hypothalamic GnRH regulates gonadotropin secretion through the pituitary GnRH type I receptor via activation of G(q). In-depth studies have identified amino acid residues in both the ligand and receptor involved in binding, receptor activation, and translation into intracellular signal transduction. Although the predominant coupling of the type I GnRH receptor in the gonadotrope is through productive G(q) stimulation, signal transduction can occur via other G proteins and potentially by G protein-independent means. The eventual selection of intracellular signaling may be specifically directed by variations in ligand structure. A second form of GnRH, GnRH II, conserved in all higher vertebrates, including man, is present in extrahypothalamic brain and many reproductive tissues. Its cognate receptor has been cloned from various vertebrate species, including New and Old World primates. The human gene homolog of this receptor, however, has a frame-shift and stop codon, and it appears that GnRH II signaling occurs through the type I GnRH receptor. There has been considerable plasticity in the use of different GnRHs, receptors, and signaling pathways for diverse functions. Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs.

GnRH is the pivotal hypothalamic hormone regulating reproduction. Over 20 forms of the decapeptide have been identified in which the NH2- and COOH-terminal sequences, which are essential for receptor binding and activation, are conserved. In mammals, there are two forms, GnRH I which regulates gonadotropin and GnRH II which appears to be a neuromodulator and stimulates sexual behaviour. GnRHs also occur in reproductive tissues and tumours in which a paracrine/autocrine role is postulated. GnRH agonists and antagonists are now extensively used to treat hormone-dependent diseases, in assisted conception and have promise as novel contraceptives. Non-peptide orally-active GnRH antagonists have been recently developed and may increase the flexibility and range of utility. As with GnRH, GnRH receptors have undergone co-ordinated gene duplications such that cognate receptor subtypes for respective ligands exist in most vertebrates. Interestingly, in man and some other mammals (e.g. chimp, sheep and bovine) the Type II GnRH receptor has been silenced. However, GnRH I and GnRH II still appear to have distinct roles in signalling differentially through the Type I receptor (ligand-selective-signalling) to have different downstream effects. The ligand-receptor interactions and receptor conformational changes involved in receptor activation have been partly delineated. Together, these findings are setting the scene for generating novel selective GnRH analogues with potential for wider and more specific application.

Gonadotropin-releasing hormone (GnRH) plays a central role in vertebrate reproduction. The evolutionary origin of this neuropeptide and its receptor is not obvious, but the advent of genomics makes it possible to examine the roots of GnRH and delve deeper into its ancestral relationships. New peptide sequences identified in invertebrates from annelids to tunicates reveal GnRH-like peptides of 10-12 amino acids. Structural conservation suggests homology between the 15 known invertebrate peptides and the 15 known vertebrate GnRHs. The functions of the invertebrate GnRH-like peptides are not necessarily related to reproduction. We suggest that structurally related families of invertebrate peptides including corazonin and adipokinetic hormone (AKH) form a superfamily of neuropeptides with the GnRH family. GnRH receptors have also been identified in invertebrates from annelids to tunicates suggesting that the origin of GnRH and its receptor extends deep in evolution to the origin of bilaterian animals. To resolve the relationship of invertebrate and vertebrate receptors, we conducted large-scale phylogenetic analysis using maximum likelihood. The data support a superfamily that includes GnRH, AKH and corazonin receptors derived from both published sequences and unpublished gene model predictions. Closely related to the GnRHR superfamily is the vasopressin/oxytocin superfamily of receptors. Phylogenetic analysis suggests a shared ancestry with deep roots. A functional role for GnRH in vertebrates or invertebrates leads to questions about the evolutionary origin of the pituitary. Our analysis suggests a functioning pituitary was the result of genomic duplications in early vertebrates. Copyright © 2010 Elsevier Inc. All rights reserved.