Gonadotropin-inhibitory hormone (GnIH), GnIH receptor and cell signaling

Gonadotropin-inhibitory hormone (GnIH) is an inhibitor of gonadotropin synthesis and release, which was originally identified in the hypothalamus of the Japanese quail (Coturnix japonica). The GnIH precursor polypeptide encodes one GnIH and two GnIH related peptides (GnIH-RP-1 and GnIH-RP-2) in birds that share the same C-terminal LPXRFamide (X=L or Q) motif. The receptor for GnIH is thought to be the G protein-coupled receptor 147 (GPR147) which has been shown to couple predominantly through the Gαi protein to inhibit cAMP production. The crude membrane fraction of COS-7 cells transfected with GPR147 cDNA specifically bound GnIH and GnIH-RPs in a concentration-dependent manner. Scatchard plot analysis of the binding showed that GPR147 possessed a single class of high-affinity binding sites. GnIH neurons project to the median eminence to control anterior pituitary function and GPR147 is expressed in the gonadotropes. GnIH neurons also project to gonadotropin-releasing hormone (GnRH)-I and GnRH-II neurons, and GnRH-I and GnRH-II neurons express GPR147. Thus, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH-I neurons as well as directly inhibiting the effects of GnRH on gonadotropes. GnIH may also partially inhibit reproductive behaviors by inhibiting GnRH-II neurons. GnIH and GPR147 are also expressed in the gonads, possibly acting in an autocrine/paracrine manner. The cell signaling process of GPR147 was extensively studied using LβT2 cells, a mouse gonadotrope cell line. In this cell line, mouse GnIH inhibits GnRH-induced gonadotropin subunit, LHβ, FSHβ, and common α, gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA dependent ERK pathway. This review summarizes the functions of GnIH, GnIH receptor and its cell signaling processes in birds and discusses related findings in mammals.