Review: evolution of GnIH and related peptides structure and function in the chordates

Abstract

Discovery of gonadotropin-inhibitory hormone (GnIH) in the Japanese quail in 2000 was the first to demonstrate the existence of a hypothalamic neuropeptide inhibiting gonadotropin release. We now know that GnIH regulates reproduction by inhibiting gonadotropin synthesis and release via action on the gonadotropin-releasing hormone (GnRH) system and the gonadotrope in various vertebrates. GnIH peptides identified in birds and mammals have a common LPXRF-amide (X = L or Q) motif at the C-terminus and inhibit pituitary gonadotropin secretion. However, the function and structure of GnIH peptides are diverse in fish. Goldfish GnIHs possessing a C-terminal LPXRF-amide motif have both stimulatory and inhibitory effects on gonadotropin synthesis or release. The C-terminal sequence of grass puffer and medaka GnIHs are MPQRF-amide. To investigate the evolutionary origin of GnIH and its ancestral structure and function, we searched for GnIH in agnathans, the most ancient lineage of vertebrates. We identified GnIH precursor gene and mature GnIH peptides with C-terminal QPQRF-amide or RPQRF-amide from the brain of sea lamprey. Lamprey GnIH fibers were in close proximity to GnRH-III neurons. Further, one of lamprey GnIHs stimulated the expression of lamprey GnRH-III peptide in the hypothalamus and gonadotropic hormone β mRNA expression in the pituitary. We further identified the ancestral form of GnIH, which had a C-terminal RPQRF-amide, and its receptors in amphioxus, the most basal chordate species. The amphioxus GnIH inhibited cAMP signaling in vitro. In sum, the original forms of GnIH may date back to the time of the emergence of early chordates. GnIH peptides may have had various C-terminal structures slightly different from LPXRF-amide in basal chordates, which had stimulatory and/or inhibitory functions on reproduction. The C-terminal LPXRF-amide structure and its inhibitory function on reproduction may be selected in later-evolved vertebrates, such as birds and mammals.

Effects of psychological stress on male fertility

“…88 Mammalian GnIH is also known as RFamide-related peptide (RFRP). 89 Two forms of GnIH (RFRP-1 and RFRP-3) have been identified in the human hypothalamus and are able to regulate the HPG axis in men. 90 Hinuma et al 91 identified a specific receptor for mammalian GnIH that was identical to the previously-described receptor, GPR147.…”

“…92 The molecular details of GnIH are eloquently described elsewhere. 89,90 GnIH neurons are situated in the dorsomedial hypothalamic area in mammals and the PVN in birds. 90 GnIH axon terminals project into the preoptic area where they come in contact with GnRH neurons, and GPR147 has been identified in GnRH neurons, suggesting that direct inhibition occurs.…”

Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors

“…Syntenic analysis involves the comparison of the locations of orthologous or paralogous genes between chromosomes, within or among species, which facilitates more accurate analyses of the origins and relationships of individual peptide-7TMR families (Cerda-Reverter et al ., 2000; Lagerstrom et al ., 2005; Lee et al ., 2009; Kim et al ., 2011, 2012; Dores, 2013; Osugi et al ., 2014). However, small scale synteny analysis is only suitable for determining the evolutionary history of closely related families.…”

Editorial: A Comparative Survey of the RF-Amide Peptide Superfamily

“…They also underline some neuropeptide families (e.g., CCK/sulfakinins) in which the RFamide motif is unique to protostomian members. Osugi et al ( 12 ) show that identification of GnIH in agnathans (lamprey) and amphioxus reveals that the C-terminal amide motif of GnIH can differ, being QPQRF or RPQRF, in addition to previously observed LPXRF in birds, mammals and most of fish, and MPQRF in grass puffer and medaka.…”

“…The review by Ayachi and Simonin ( 21 ) presents the emerging evidences in rodents that all RF-amide peptides and their receptors are involved in the modulation of nociception in basal and chronic pain conditions, as well as of opioid-induced hyperalgesia. The reviews on GnIH by Osugi et al ( 12 ) and by Ogawa and Parhar ( 22 ) report that even if the inhibitory role of GnIH is well established in later-evolved vertebrates, such as birds and mammals, the situation is less clear in teleosts and may vary according to the maturational stage. Comparative studies have the potential to reveal novel regulatory mechanisms that could give a better comprehension of physiological functions.…”