Edited by: Honoo Satake, Suntory Foundation for Life Sciences, Japan
Reviewed by: Gregoy Y. Bedecarrats, University of Guelph, Canada; Kazuyoshi Ukena, Hiroshima University, Japan
Specialty section: This article was submitted to Experimental Endocrinology, a section of the journal Frontiers in Endocrinology
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Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of gonadotropin-releasing hormone (GnRH) neurons. GnIH is also called RFamide-related peptide in mammals or LPXRFamide peptide in fishes due to its characteristic C-terminal structure. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. Although most of the studies in mammals, birds, and fish have shown the inhibitory action of GnIH in the hypothalamic–pituitary–gonadal (HPG) axis, several
Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was initially isolated from the brain of Japanese quail, which decreases luteinizing hormone (LH) concentration in the culture medium of the anterior pituitary gland (
Human RFRP-1 and -3 (
Amino-acid sequences of RFRPs, GnIHs, and LPXRFa peptides in chordates.
Animal | Name | Sequence | Reference | |
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Mammals | Human | RFRP-1 | ( |
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RFRP-3 | ( |
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Macaque | RFRP-1 |
( |
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RFRP-3 | ( |
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Bovine | RFRP-1 | ( |
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RFRP-3 | ( |
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Horse | RFRP-3 |
( |
||
Rat | RFRP-1 |
( |
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RFRP-3 | ( |
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Siberian hamster | RFRP-1 | ( |
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RFRP-3 | ( |
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Syrian hamster | RFRP-1 |
( |
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RFRP-3 |
( |
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Birds | Quail | GnIH | ( |
|
GnIH-RP-1 |
( |
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GnIH-RP-2 | ( |
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Chicken | GnIH | ( |
||
GnIH-RP-1 |
( |
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GnIH-RP-2 |
( |
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White-crowned sparrow | GnIH |
( |
||
GnIH-RP-1 |
( |
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GnIH-RP-2 |
( |
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European starling | GnIH | ( |
||
GnIH-RP-1 |
( |
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GnIH-RP-2 |
( |
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Zebra finch | GnIH | ( |
||
GnIH-RP-1 |
( |
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GnIH-RP-2 |
( |
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Reptiles | Anole lizard | GnIH |
ENSACAG00000013069 | |
GnIH-RP-1 |
ENSACAG00000013069 | |||
GnIH-RP-2 |
ENSACAG00000013069 | |||
Red-eared slider turtle | GnIH | 15 | ||
GnIH-RP-1 | 15 | |||
GnIH-RP-2 | 15 | |||
Chinese softshell turtle | GnIH |
ENSPSIG00000017952 | ||
GnIH-RP-1 |
ENSPSIG00000017952 | |||
GnIH-RP-2 |
ENSPSIG00000017952 | |||
Amphibians | Bullfrog | fGRP/R-RFa | ( |
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fGRP-RP-1 | ( |
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fGRP-RP-2 | ( |
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fGRP-RP-3 | ( |
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Red-bellied newt | nLPXRFa-1 | ( |
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nLPXRFa-2 | ( |
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nLPXRFa-3 | ( |
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nLPXRFa-4 | ( |
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Teleost fish | Goldfish | gfLPXRFa-1 |
( |
|
gfLPXRFa-2 |
( |
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gfLPXRFa-3 | ( |
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Medaka | mdLPXRFa-1 |
XM_004073848 | ||
mdLPXRFa-2 |
XM_004073848 | |||
mdLPXRFa-3 |
XM_004073848 | |||
Grass puffer | LPXRFa-1 |
( |
||
LPXRFa-2 |
( |
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RYa |
( |
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Tiger puffer | LPXRFa-1 |
( |
||
LPXRFa-2 |
( |
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RYa |
( |
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Agnathans | Sea lamprey | lLPXRFa-1a | ( |
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lLPXRFa-1b | ( |
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lLPXRFa-2 | ( |
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Protochordates | Amphioxus | PQRFa-1 | ( |
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PQRFa-2 | ( |
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PQRFa-3 | ( |
Yin et al. characterized the binding activity of quail GnIH and GnIH-RPs to a G-protein-coupled receptor (GPCR) GPR147. The membrane fraction of COS-7 cells transfected with quail GPR147 cDNA specifically bound GnIH and GnIH-RPs that have a C-terminal LPXRFa motif with similar affinities (
Gonadotropin-inhibitory hormone peptides suppress the production of cAMP by binding to GPR147 on the cells, suggesting that GPR147 couples to Gαi protein that inhibits adenylate cyclase (AC) (
Effect of GnIH on the HPG axis of mammals.
Concentration or dose of peptides | Rout of administration, culture medium | Administration time, sample collection, measurement | Effect | Reference | |
---|---|---|---|---|---|
Postmenopausal women | 50-µg/kg/h human RFRP-3 | iv | Continuous administration for 3 h | LH secretion was decreased during RFRP-3 administration | George et al. ( |
Estrous ewes | 1-mg/h human RFRP-3 | iv | 2-h infusion | LH secretion was decreased during and after RFRP-3 administration | Clarke et al. ( |
Ovariectomized ewes treated with EB to induce LH surge | 1-mg bolus + 0.5 mg/h human RFRP-3 | iv | 8-h infusion | EB-induced LH surge was blocked by RFRP-3 | Clarke et al. ( |
Hypothalamo-pituitary disconnected ovariectomized ewes | 50, 100, 200 ng GnRH during 400-µg/h human RFRP-3 | iv | Blood was collected −5, 5, 10, 15, 20, 30 min after GnRH administration | RFRP-3 decreased 100-ng GnRH-induced LH secretion | Smith et al. ( |
Castrated male calves | 90-µg bovine RFRP-3 | iv | 6 injections at 10-min intervals | LH pulse frequency was decreased during 1-h injection period | Kadokawa et al. ( |
Male rats | 10, 100, 500 ng rat RFRP-3 | icv | Blood was collected 20 min after administration | LH concentration was decreased by administration of 10-, 100-, or 500-ng RFRP-3 | Johnson et al. ( |
Male rats | 0.1, 0.5, 1, 5 nmol rat RFRP-3 | icv | Blood was collected 15–120 min after administration | Total LH secretion until 120 min after administration was decreased by 5-nmol RFRP-3. FSH concentration was decreased at 15 min by 5-nmol RFRP-3. Total FSH secretion until 120 min after administration was decreased by 5-nmol RFRP-3 | Pineda et al. ( |
Gonadectomized male rats | 0.1, 0.5, 1, 5 nmol rat RFRP-3 | icv | Blood was collected 15–120 min after administration | LH concentration was decreased at 15 min by 5-nmol RFRP-3. Total LH secretion until 120 min after administration was decreased by 1- and 5-nmol RFRP-3. Total FSH secretion until 120 min after administration was decreased by 5-nmol RFRP-3 | Pineda et al. ( |
Gonadectomized male rats | 10-nmol rat RFRP-3 | iv | Blood was collected 15–120 min after administration | LH concentration was decreased at 60 min. Total LH secretion until 75 min after administration was decreased. FSH concentration was decreased at 60 and 75 min after administration | Pineda et al. ( |
Ovariectomized rats | 1, 5 nmol rat RFRP-3 | icv | Blood was collected 15–120 min after administration | LH concentration was decreased at 15 min by 1-nmol RFRP-3. Total LH secretion until 120 min after administration was decreased by 5-nmol RFRP-3 | Pineda et al. ( |
Ovariectomized rats | 1-µg rat RFRP-3 | iv | Blood was collected 30, 60, 120 min after administration | LH concentration was decreased 120 min after administration | Murakami et al. ( |
Ovariectomized rats with E2 + P4 to induce LH surge | 2.5, 25 ng/h rat RFRP-3 | icv using osmotic pump | Brains were collected 2 days later at the surge peak | 25-ng/h 25-ng/h RFRP-3-reduced c-Fos expression in GnRH neurons and anteroventral periventricular region that provides stimulatory input to GnRH neurons | Anderson et al. ( |
Prepubertal female mice | 100, 500, 1,000 ng RFRP-3 | icv | Hypothalamus and blood was collected 4 h after administration | GnRH mRNA, Kiss1 mRNA, and LH concentration was decreased by 500- and 1,000-ng RFRP-3 | Xiang et al. ( |
Ovariectomized or E2-treated ovariectomized prepubertal or adult female mice | 20-nmol RFRP-3 | icv | Blood was collected 4 h after administration | RFRP-3 decreased LH concentration in only E2-treated ovariectomized prepubertal female mice but both E2-treated or not treated ovariectomized adult female mice | Xiang et al. ( |
Male Syrian hamsters | 150, 500, 1,500, 5,000-ng Syrian hamster RFRP-3 | icv | Blood was collected 30 and 120 min after administration | Ancel et al. ( |
|
Male Syrian hamsters acclimatized to SD | 12-µg/day Syrian hamster RFRP-3 | icv using osmotic pump | Blood was collected after 5 weeks of continuous administration | Ancel et al. ( |
|
Ovariectomized Syrian hamsters | 100, 300, 500 ng GnIH (icv), 600-ng GnIH (ip) | icv, ip | Blood was collected 5 (icv), 30 (icv and ip) min after administration | LH concentration was decreased 5 and 30 min after icv administration of 500-ng GnIH, and 30 min after ip administration of 600-ng GnIH. | Kriegsfeld et al. ( |
Male Siberian hamsters acclimatized to LD or SD | 100- and 500-pmol Siberian hamster RFRP-1 or RFRP-3 | icv | Blood was collected 5 and 30 min after administration | LH concentration was decreased 5 and 30 min after administration of 500-pmol RFRP-1, 100- and 500-pmol RFRP-3, 30 min after administration of 100-pmol RFRP-1 in LD. |
Ubuka et al. ( |
Hypothalamic tissue of male mice | 10−7, 10−6 M RFRP-3 with 10−6 M kisspeptin | Medium 199 | After 1-h incubation medium was collected. | 10−6 M RFRP-3 suppressed 10−6 M kisspeptin-induced GnRH release | Son et al. ( |
Hypothalamic tissue of female mice | 10−6 M RFRP-3 with 10−6 M VIP | Medium 199 | After 1-h incubation medium was collected. | 10−6 M RFRP-3 suppressed 10−6 M VIP-induced GnRH release | Son et al. ( |
GFP labeled GnRH neurons of transgenic mice | 0.01–1-µM GnIH or RFRP-3 | aCSF | 15-s application | GnIH and RFRP-3 produced a non-desensitizing hyperpolarization [IC50: 34 nM (GnIH), 37 nM (RFRP-3)] |
Wu et al. ( |
GFP labeled GnRH neurons of transgenic mice | 1-µM RFRP-3 | aCSF | 5-min application | RFRP-3 exhibited rapid and repeatable inhibitory effects on the firing rate of 41% of GnRH neurons. |
Ducret et al. ( |
Mouse GnRH neuronal cell line (GT1–7) | 10−10, 10−9, 10−8, 10−7, 10−6 M RFRP-1 and -3 with 10−6 M VIP | DMEM | 6 (CRE assay) or 1 (p38, ERK assay) h application | 10−6 M VIP-induced CRE activity was suppressed by 10−8, 10−7, 10−6 M RFRP-1, 3. 10−6 M VIP-induced p38 and ERK phosphorylation was suppressed by 10−7, 10−6 M RFRP-3 | Son et al. ( |
Mouse GnRH neuronal cell line (mHypoA-GnRH/GFP) | 10-, 100-nM human RFRP-3 | DMEM | 1-, 2-, 4-h application | GnRH mRNA expression was decreased by 100-nM RFRP-3 at 1-, 2-, 4-h application | Gojska et al. ( |
Ewe dispersed pituitary cells | 10−14, 10−12, 10−10, 10−8 M human RFRP-3 with 10−9 M GnRH | DMEM | Medium was collected after 2-h incubation | GnRH-induced LH release was decreased by 10−12, 10−10, 10−8 M RFRP-3. GnRH-induced FSH release was decreased by 10−10, 10−8 M RFRP-3 | Clarke et al. ( |
Gonadectomized ewe and ram dispersed pituitary cells | 10−12, 10−9 M human RFRP-3 with 10−9 M GnRH | DMEM with 10% fetal calf serum | Medium was collected 8, 16, 24 h during incubation and finally pituitary cells were collected | GnRH-induced LH release was decreased by 10−12, 10−9 M RFRP-3 at 8-, 16-, 24-h in ewe pituitary cells. GnRH-induced LH release was decreased by 10−12, 10−9 M RFRP-3 at 8-, 16-h in ram pituitary cells. GnRH-induced FSH release was decreased by 10−12, 10−9 M RFRP-3 at 16-, 24-h in ewe pituitary cells. GnRH-induced FSH release was decreased by 10−12, 10−9 M RFRP-3 at 8-, 16-h in ram pituitary cells. GnRH-induced LHβ, FSHβ expression, ERK phosphorylation were decreased by 10−12, 10−9 M RFRP-3 in ewe and ram pituitary cells | Sari et al. ( |
Cattle dispersed pituitary cells | 10−12, 10−10, 10−8, 10−6 M bovine RFRP-3 with 10−9 M GnRH | DMEM | Medium was collected after 2-h incubation | 10−10, 10−8, 10−6 M RFRP-3 decreased GnRH-induced LH release | Kadokawa et al. ( |
Gonadectomized male rat pituitaries | 10−10, 10−8, 10−6 M rat RFRP-3 with or without 10−9 M GnRH | DMEM | After 2-h incubation medium was collected | Basal LH concentration was decreased by 10−8, 10−6 M RFRP-3. LH concentration stimulated by GnRH was decreased by 10−10, 10−8 M RFRP-3. | Pineda et al. ( |
Female rat dispersed pituitary cells | 10−16, 10−14, 10−12 M rat RFRP-3 with 10−9 M GnRH | DMEM with 10% fetal bovine serum | After 24-h incubation medium was collected | LH concentration stimulated by GnRH was decreased by 10−12 M RFRP-3 | Murakami et al. ( |
Mouse gonadotrope cell line (LβT2) | 10−7, 10−6 M RFRP-3 with 10−7 M GnRH | DMEM | 1 h (gonadotropin subunit gene expression), 2 h (LH release) application | 10−7 M GnRH-induced gonadotropin subunit gene expression was suppressed by 10−6 M RFRP-1, 3. 10−8 M GnRH-induced LH release was suppressed by 10−7, 10−6 M RFRP-1, 3 | Son et al. ( |
Mouse gonadotrope cell line (LβT2) | 10−9, 10−8, 10−7, 10−6 M RFRP-3 with 10−7 M GnRH | DMEM | 75-min (cAMP assay), 6-h (CRE assay) or 15-min (ERK assay) application | 10−7 M GnRH-induced cAMP production was suppressed by 10−7, 10−6 M RFRP-1, 3. 10−7 M GnRH-induced CRE activity was suppressed by 10−8, 10−7, 10−6 M RFRP-1, 3. 10−7 M GnRH-induced ERK phosphorylation was suppressed by 10−6 M RFRP-1, 3 | Son et al. ( |
Son et al. further investigated the signal transduction pathway that conveys the inhibitory action of GnIH in GnRH neurons by using a mouse GnRH neuronal cell line, GT1–7 (
Gonadotropin-inhibitory hormone precursor mRNA is expressed in the hypothalamus of all vertebrates investigated (
Schematic diagram of the mechanism of gonadotropin-inhibitory hormone (GnIH) action in the hypothalamic–pituitary–gonadal axis. GnIH neurons act on aromatase and gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus and gonadotrope in the pituitary
Abundant GnIH-immunoreactive (ir) fibers exist in the median eminence of humans (
An electrophysiological study has shown that RFRP-3 exhibits rapid and repeatable inhibitory effects on the firing of 41% of GnRH neurons in adult mice (
To understand the physiological roles of GnIH in mammalian reproduction, GnIH precursor cDNA and endogenous mature peptides have been identified in the Siberian hamster brain (
Moussavi et al. investigated the effect of intraperitoneal (ip) administration of goldfish LPXRFa-3 on LHβ and FSHβ subunit mRNA levels in the pituitary and serum LH concentration during gonadal cycle in goldfish (
Effect of GnIH on the HPG axis of amphioxus, lamprey, and teleost fishes.
Concentration or dose of peptides | Culture medium, rout of administration | Administration time, sample collection, measurement | Effect | Reference | |
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European sea bass | 1, 2, 4 µg sea bass GnIH-1, 2 | icv | 6 h after administration brain, pituitary, and blood were collected | GnRH1 mRNA level in the brain was decreased by 1, 2, 4 µg GnIH-1. GnRH2 mRNA level in the brain was decreased by 1, 2, 4 µg GnIH-2. Kiss1 mRNA level in the brain was decreased by 2-µg GnIH-2. Kiss2 mRNA level in the brain was decreased by 2, 4 µg GnIH-2. Kiss1 receptor mRNA level in the brain was decreased by 2-µg GnIH-2. GnIH mRNA level in the brain was decreased by 1, 2 µg GnIH-2. GnIH receptor mRNA level in the brain was decreased by 1, 2 µg GnIH-2. LHβ mRNA level in the pituitary was decreased by 1, 2, 4 µg GnIH-2. FSHβ mRNA level in the pituitary was decreased by 2, 4 µg GnIH-2. GnRH receptor II1a mRNA level in the pituitary was decreased by 2, 4 µg GnIH-2. Plasma LH level was decreased by 4-µg GnIH-1 and 1-µg GnIH-2 | Paullada-Salmerón et al. ( |
Goldfish | 2-µg goldfish LPXRFa-3 | ip | Injected twice with 12-h interval and pituitaries and blood were collected 12 h after the second injection | Moussavi et al. ( |
|
Goldfish | 2-µg goldfish LPXRFa-3 | ip | Injected twice with 12-h interval with or without 4-µg sGnRH or cGnRH-II and pituitaries and blood were collected 2 h after the second injection | Moussavi et al. ( |
|
Sexually mature female goldfish | 1-µg/g bw zebrafish LPXRFa-3 | ip | Injected twice with 3-h interval and blood was collected 1 and 3 h after the second injection | Serum LH concentration was decreased by LPXRFa-3 either at 1 and 3 h after the second injection | Zhang et al. ( |
Female goldfish at late vitellogenic stage | 100-ng/g bw goldfish LPXRFa-2, 3 | ip | After 12-h administration hypothalamus and pituitary were collected | sGnRH mRNA level in the hypothalamus was decreased by LPXRFa-2, 3. LHβ mRNA level in the pituitary was decreased by LPXRFa-2. FSHβ mRNA level in the pituitary was decreased by LPXRFa-2, 3 | Qi et al. ( |
Immature, mature male and female cinnamon clownfish | 100-ng/g bw goldfish LPXRFa-3 | ip | After 0, 6, 12, and 24-h administration with or without 100-ng/g bw sbGnRH brain, pituitary and blood were collected | GnIH and GnIH receptor mRNA levels in the brain were increased at 6, 12 and 24 h. |
Choi et al. ( |
Female orange-spotted grouper | 100-ng/g bw grouper GnIH-I, II, III | ip | Injected twice with 6-h interval and hypothalamus and pituitary were collected 6 h after the second injection | GnRH1 mRNA level in the hypothalamus was decreased by grouper GnIH-I, II, III. |
Wang et al. ( |
Lamprey | 50, 100 µg/kg bw lamprey LPXRFa-1a, 1b, 2 | ip | Injected twice with 24-h interval and brain and pituitary were collected 48 h after the second injection | Osugi et al. ( |
|
European sea bass | 1-µg sea bass GnIH-1, 2/g bw in coconut oil | im | Injected on day 17 from October to January and blood was collected on day 22 from October to January. Brain and pituitary were collected on day 17 of February (spermiation stage) | Plasma testosterone and 11-ketotestosterone levels were decreased by sbGnIH-1, 2 in November and December (early and mid-spermatogenesis). |
Paullada-Salmerón et al. ( |
Flatfish | 0.1, 1 µg/g bw flatfish GnIH-2, 3 | im | Injected twice with 12-h interval and brain and pituitary were collected 4 and 8 h after the second injection | GnRH3 mRNA level in the brain was decreased by 1-µg/g bw GnIH-3 at 4 h after administration. LHβ mRNA level in the pituitary was decreased by 0.1, 1 µg/g bw GnIH-3 at 4 h after administration | Aliaga-Guerrero et al. ( |
Primary culture of male zebrafish pituitary | 10−12, 10−11, 10−10, 10−9 M zebrafish LPXRFa-3 | Culture media | After 18-h incubation pituitary was collected | Common α mRNA level was decreased by 10−12, 10−11, 10−10 M LPXRFa-3. LHβ mRNA level was decreased by 10−11, 10−10 M LPXRFa-3 | Spicer et al. ( |
Primary culture of grass puffer pituitary | 10−9, 10−7 M goldfish LPXRFa-1 | RPMI medium | After 48-h administration pituitaries were collected | Shahjahan et al. ( |
|
Primary culture of |
10−8, 10−6 M |
Leibovitz L-15 medium with 10% fetal bovine serum | After 24-h incubation medium was collected | LH and FSH concentration was decreased by 10−6 M LPQRFa-1. |
Di Yorio et al. ( |
Primary culture of male Nile tilapia pituitary | 10−9, 10−8, 10−7, 10−6 M Pyroglutamic-tilapia LPXRFa-2 | Culture medium | After 6-h incubation medium was collected | Biran et al. ( |
|
Dispersed goldfish pituitary cells | 10−9, 10−8, 10−7 M goldfish LPXRFa-3 | Medium 199 with 1% horse serum | After 12-h administration medium and cells were collected | LHβ mRNA level was decreased by 10−8 and 10−7 M LPXRFa-3 at early gr, |
Moussavi et al. ( |
Dispersed female goldfish pituitary cells | 10−7 M goldfish LPXRFa-2, 3 | Medium 199 with 10% fetal bovine serum | After 12-h administration with 10−7 M LHRH-A cells were collected | FSHβ mRNA level increased by LHRH-A was decreased by 10−7 M LPXRFa-3. | Qi et al. ( |
Dispersed male sockeye salmon pituitary cells | 10−9, 10−7, 10−5 M goldfish LPXRFa-1, 2, 3 | MEM | After 2-h administration medium was collected | Amano et al. ( |
|
COS-7 cells transfected with orange-spotted grouper GnIH receptor | 10−10, 10−9, 10−8, 10−7, 10−6 M grouper GnIH-I, -II, -III | DMEM with 10% fetal bovine serum | After 24-h incubation CRE or SRC-luciferase activity was measured | Forskolin-induced CRE-luciferase activity was decreased by 10−9, 10−8, 10−7, 10−6 M grouper GnIH-I, II and 10−6 M grouper GnIH-III. SRE-luciferase activity was decreased by 10−9, 10−7, 10−6 M grouper GnIH-I | Wang et al. ( |
COS-7 cells transfected with amphioxus PQRFa receptor 1 | 10−7, 10−6 M amphioxus PQRFa-1, 2, 3 | DMEM | After 6-h administration CRE-luciferase activity was measured | Forskolin-induced CRE-luciferase activity was decreased by 10−6 M PQRFa-1, 2, and 10−7, 10−6 M PQRFa-3 | Osugi et al. ( |
Ip administration of grouper GnIH-I, II, and III decreased GnRH1 mRNA level in the hypothalamus (
In addition, 48-h incubation of grass puffer pituitary with LPXRFa-1 (10−7 M) increased LHβ and FSHβ mRNA levels [(
Effect of goldfish LPXRFa-3 on gonadotropin synthesis and release was tested in dispersed goldfish pituitary cells collected at different gr stages (
The mechanism of GnIH (RFRP-3) effect on the electrophysiological activity of GnRH neurons was studied in transgenic mice having vesicular glutamate transporter 2 (vGluT2)-GnRH neurons (
It is known that E2 secreted from the ovary negatively and positively act on the hypothalamus and pituitary to regulate the HPG axis in females. However, it is also known that E2 is synthesized from androgen by aromatase neurons in the hypothalamus (
Binding of GnRH with GnRH receptor on gonadotropes results in the activation of intracellular Gαq/11 and phospholipases and generation of the second messengers, inositol 1-, 4-, 5-tris-phosphate, diacylglycerol, and arachidonic acid, which stimulate Ca2+ mobilization and PKC activity. Ca2+ mobilization initiates gonadotropin release (Figure
However, recent studies of GPCR have shown that GPCR not only functions as a monomer or homodimer but also as a heterodimer with different GPCR resulting in modulation of ligand binding affinity, signal transduction, and internalization of the receptors (
A recent study has shown that centrally administered GnIH can decrease plasma LH concentration in ovariectomized (OVX) prepubertal female mice that were treated with E2 but not in OVX mice that were not treated with E2 (
Finally, it is known for a long time that binding of GnRH with GnRH receptors is followed by aggregation, complex formation and internalization (
Complex mechanism may be involved in
Gonadotropin-inhibitory hormone orthologous peptides have a characteristic LPXRFamide C-terminal motif in most vertebrate species, which is critical for receptor binding. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. GnIH generally decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of GnRH neurons. However, one study shows stimulatory effects of GnIH on the electrophysiological activity of some GnRH neurons in mice (
TU wrote the manuscript and IP edited the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.