gonadotropin-inhibitory hormone

Discovery

The structure and its physiological function were first identified in the Japanese quail in 2000. GnIH has also been characterized in various vertebrates, including humans.

Regulation of synthesis and release

GnIH expression in the brain is regulated by the nocturnal secretion of melatonin in birds and mammals. Melatonin may also stimulate GnIH release. GnIH expression in the brain is also regulated by stress via the action of glucocorticoids.- Although glucocorticoid response elements (GREs) are found at -1665 and -1530 bp upstream of the GnIH precursor coding region in rats, the -1530 GRE was identified to be critical for corticosterone responsiveness and recruitment of the glucocorticoid receptor (GR). GnIH expression in the testis is also regulated by melatonin and corticosterone in birds.

Signal transduction pathway

Mammalian GnIH (RFRP) suppresses cAMP production in Chinese hamster ovarian cells transfected with GnIHR (GPR147) cDNA, suggesting that GPR147 couples to the Gαi protein. The cell signaling pathway by GnIH and GnIHR (GPR147) and its possible interaction with gonadotropin-releasing hormone (GnRH) signaling was investigated using a mouse gonadotrope cell line, LβT2. The results indicated that mouse GnIH peptides (mRFRPs) inhibit GnRH-induced gonadotropin subunit gene transcriptions by inhibiting AC/cAMP/ PKA-dependent ERK activation in LβT2 cells.

Clinical implications

Two endogenous human GnIH peptides, human GnIH1 (RFRP-1) and GnIH2 (RFRP-3), were identified in the human hypothalamus. It was demonstrated that human RFRP-3 has a potent inhibitory action on gonadotropin secretion in ovines that has the same RFRP-3 aa sequence in its GnIH precursor polypeptide. Many factors, such as stress, anorexia, diabetes, obesity, and photoperiod, inhibit gonadotropin secretion.The possible role of GnIH in mediating these effects has been implicated in animal models. Thus, GnIH has the potential of an alternative or adjunct therapeutic agent to inhibit gonadotropins and steroid hormones.

Description

Gonadotropin-inhibitory hormone, a hypothalamic neuropeptide inhibiting gonadotropin secretion. GnIH inhibits sociosexual and aggressive behavior. It has an LPXRFamide (X?L or Q) sequence at its C-terminal.

Industrial uses

The endogenous inhibitor of gonadotropin secretion, GnIH, has therapeutic potential in the treatment of gonadotropins or steroid hormone-dependent diseases, such as precocious puberty, endometriosis, uterine fibroids, benign prostatic hyperplasia, and prostatic and breast cancers. Human GnIH may also have potential as a novel contraceptive.

Biological Activity

Human GnIH1 (RFRP-1): Mr 1,429, pI 10.55. Freely soluble in water. Human GnIH1 (RFRP-1) dissolved in water at 10^-3 M is stable for more than a year at - 20°C. Human GnIH2 (RFRP-3): Mr 969, pI 10.55. Freely soluble in water. Human GnIH2 (RFRP-3) dissolved in water at 10^{- 3} M is stable for more than a year at - 20°C.

Structure and conformation

Most GnIH peptides have the LPXRFamide (X?L or Q) motif at their C-termini . Although the N-terminal sequences are less conserved across vertebrate species, it has been observed that many identified endogenous GnIH peptides start from serine at the N-terminal (macaque RFRP-3, bovine RFRP-1, hamster RFRP-1, quail GnIH, quail GnIH-RP-2, starling GnIH, zebra finch GnIH, frog GRP, frog GRP-RP-1, newt LPXRFa-1, newt LPXRFa-3, goldfish LPXRFa-3, lamprey LPXRFa-1a, and lamprey LPXRFa-2). Other GnIH peptides start from alanine (bovine RFRP-3, rat RFRP-3, frog GRP-RP-3, newt LPXRFa-4, and lamprey LPXRFa-1b), methionine (human RFRP-1, newt LPXRFa-2), valine (human RFRP-3), threonine (hamster RFRP-3), and tyrosine (frog GRP-RP-2) at their N-termini.