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Questions And Answer

• Discovery

  In 1971, GnRH was first isolated from the porcine and ovine by Schally1 and Guillemin, respectively. In nonmammalian vertebrates, GnRH was isolated from the chicken in 1982 and the salmon in 1983. To date, 15 different isoforms of GnRHs have been identified in vertebrates. In nonvertebrate chordates, multiple GnRH-like peptides have been identified in tunicates, first from Chelyosoma productum in 1996.;

• Structure

  Vertebrate GnRH isoforms consist of 10 aa residues with a pyroglutamic acid at the N-terminus and an amidated Gly at the C-terminus . Based on the primary structure, phylogenetic analysis, and synteny, multiple GnRH forms are classified into three paralogous groups: GnRH1, GnRH2, and GnRH3.3, 4 The peptides are bent with a β-turn around Gly6 , and the N-terminal and C-terminal amino acid residues are important for binding to the GnRH receptor (GnRH-R).5 Primary structure The primary structure of GnRH is highly conserved in the N-terminus (positions 1–4) and in the C-terminus (positions 9–10). Position 8 is the most variable.
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• Properties

  Mr 1050–1250. GnRH is inactivated in 0.9M HCl at 100°C for 60min, and is also inactivated by endopeptidases such as chymotrypsin and papain. mGnRH and cGnRH-I are soluble in water; cGnRH-II and sGnRH are insoluble in water but soluble in 10mM acetic acid.;

• Receptors

  GnRH-R is a membrane-bound GPCR belonging to the Class A (rhodopsin-like) subfamily. Two major types of GnRH-Rs—type I and type II—have been identified in vertebrates.The type I GnRH-Rs, present in mammals, coelacanth, and some cartilaginous fish, lack a C-terminal intracellular domain that is responsible for rapid desensitization, and show a strong preference for GnRH1. The type II GnRH-Rs, present in both mammalian and nonmammalian species, show a preference for GnRH2. The type II GnRH-Rs are further divided into two subtypes, IIa and IIb. In some mammals, including humans, the type II GnRH-R is a nonfunctional receptor encoded by a pseudogene. The human type I GnRH-R consists of 328 aa residues.;

• Clinical implications

  Idiopathic hypogonadotropic hypogonadism (IHH) is a family of genetic disorders that is associated with defects in the production and/or action of hypothalamic peptide, which controls GnRH. As mentioned above, IHH with anosmia is referred to as KS. In addition, the most common cause of delayed puberty is a functional defect in the production of GnRH from the hypothalamus.;

• Synthesis and release

  The regulation of GnRH secretion by internal and environmental factors such as growth, energy condition, light, photoperiod, temperature, and social status is critical for reproductive success. Regulatory mechanisms of GnRH1 neurons involve many stimulatory and inhibitory factors including gonadal steroids, neuropeptides, and neurotransmitters (GABA, glutamate, norepinephrine). Kisspeptin stimulates GnRH1 secretion and has key roles in the transmission of the negative and positive feedback effects of gonadal steroids, the metabolic regulation, and the photoperiodic control of reproduction. Gonadotrophin-inhibitory hormone (GnIH) may inhibit gonadotropin secretion by decreasing the activity of GnRH1 neurons.;

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