Abstract
Gonadotropin-inhibitory hormone (GnIH) was first identified in the Japanese quail as a hypothalamic neuropeptide inhibitor of gonadotropin secretion. Subsequent studies have shown that GnIH is present in the brains of birds including songbirds, and mammals including humans. The identified avian and mammalian GnIH peptides universally possess an LPXRFamide (X = L or Q) motif at their C-termini. Mammalian GnIH peptides are also designated as RFamide-related peptides from their structures. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which is thought to be coupled to Gαi protein. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function. GPR147 is expressed in the gonadotropes and GnIH suppresses synthesis and release of gonadotropins. It was further shown in immortalized mouse gonadotrope cell line (LβT2 cells) that GnIH inhibits gonadotropin-releasing hormone (GnRH) induced gonadotropin subunit gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA-dependent ERK pathway. GnIH neurons also project to GnRH neurons in the preoptic area, and GnRH neurons express GPR147 in birds and mammals. Accordingly, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as directly acting on the gonadotropes. GnIH also inhibits reproductive behavior possibly by acting within the brain. GnIH expression is regulated by a nocturnal hormone melatonin and stress in birds and mammals. Accordingly, GnIH may play a role in translating environmental information to inhibit reproductive physiology and behavior of birds and mammals. Finally, GnIH has therapeutic potential in the treatment of reproductive cycle and hormone-dependent diseases, such as precocious puberty, endometriosis, uterine fibroids, and prostatic and breast cancers.
Highlights
The decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion
No hypothalamic neuropeptide inhibitor of gonadotropin secretion was known in vertebrates, dopamine has been reported as an inhibitor of gonadotropin secretion in several fish groups
It is known that gonadotropin-inhibitory hormone (GnIH) and its receptor are expressed in the gonads of birds (Bentley et al, 2008; Maddineni et al, 2008; McGuire and Bentley, 2010; McGuire et al, 2011) and mammals (Zhao et al, 2010; Singh et al, 2011a,b; Li et al, 2012) including humans (Oishi et al, 2012), this review highlights the discovery of GnIH in the quail brain and the progress of GnIH research investigating its function in the brain and pituitary of birds and mammals
Summary
The decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion. In 2000, a previously unidentified hypothalamic neuropeptide was shown to inhibit gonadotropin release from the cultured quail anterior pituitary gland and it was named gonadotropin-inhibitory hormone (GnIH; Tsutsui et al, 2000). The isolated peptide was localized in the hypothalamo-hypophyseal system, and shown to decrease gonadotropin release from cultured quail anterior pituitary glands (Tsutsui et al, 2000). This RFamide peptide was named GnIH (Tsutsui et al, 2000). The GnIH precursor consisted of 173 amino acid residues that encoded one GnIH and two GnIH-related peptides (GnIH-RP-1 and GnIH-RP-2) possessing an LPXRFamide (X = L or Q) sequence at their C-termini (Figure 1). Further studies are required to investigate if GnIH and GnIH-RPs work additively or synergistically to achieve their effects on the cells that express GnIH-R
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