Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54

Roux, Nicolas de; Génin, Emmanuelle; Carel, Jean Claude; Matsuda, Fumihiko; Chaussain, J L; Milgröm, Edwin

doi:10.1073/pnas.1834399100

Cited by 2,129 publications

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“…6,7 Lack of KP signaling via the GPR-54 receptor is associated with reproductive system failure. 8 Cleavage of the KP 45−54 peptide between residues 51 and 52 by matrix metalloproteinases abolishes the activation of GPR-54 by the KP 45−54 peptide. 9 The KP 42−54 and KP 45−54 peptides also activate NPFF receptors, 10,11 and some of the actions of KP peptides could be mediated by NPFF receptor activation.…”

mentioning

confidence: 99%

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

Milton

Chilumuri

Rocha‐Ferreira

et al. 2012

ACS Chem. Neurosci.

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Alzheimer's disease (AD) onset is associated with changes in hypothalamic-pituitary−gonadal (HPG) function. The 54 amino acid kisspeptin (KP) peptide regulates the HPG axis and alters antioxidant enzyme expression. The Alzheimer's amyloid-β (Aβ) is neurotoxic, and this action can be prevented by the antioxidant enzyme catalase. Here, we examined the effects of KP peptides on the neurotoxicity of Aβ, prion protein (PrP), and amylin (IAPP) peptides. The Aβ, PrP, and IAPP peptides stimulated the release of KP and KP 45−54. The KP peptides inhibited the neurotoxicity of Aβ, PrP, and IAPP peptides, via an action that could not be blocked by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists. Knockdown of KiSS-1 gene, which encodes the KP peptides, in human neuronal SH-SY5Y cells with siRNA enhanced the toxicity of amyloid peptides, while KiSS-1 overexpression was neuroprotective. A comparison of the catalase and KP sequences identified a similarity between KP residues 42−51 and the region of catalase that binds Aβ. The KP peptides containing residues 45−50 bound Aβ, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Aβ, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides. KEYWORDS: KiSS-1, kisspeptin, amyloid-β, prion protein, amylin, neuroprotection N euroendocrine hormone changes are seen in aging, and there are disease specific changes associated with Alzheimer's disease (AD). 1,2 One of the neuroendocrine systems to show profound changes with aging is the hypothalamic−pituitary−gonadal (HPG) system, and the pathology of AD, Creutzfeldt−Jakob disease (CJD), and type 2 diabetes mellitus (T2DM) is also associated with changes in the hormones of this system. 3,4 A major regulator of the HPGaxis is the 54 amino acid kisspeptin (KP) peptide, which acts on gonadotrophin-releasing hormone (GnRH) neurons to activate GnRH release. 5 The KP peptide is produced in neurons by processing of the KiSS-1 preproprotein to yield the 54 amino acid KP peptide, which corresponds to residues 68−121 of KiSS-1. 6 Shorter derivatives of KP peptide comprising the C-terminal 14 (KP 41−54), 13 (KP 42−54), and 10 (KP 45−54) amino acids have also been found in tissues and corresponding to residues 108− 121, 109−121, and 112−121 of KiSS-1. 6,7 Biological activity of KP peptides requires the KP 45−54 sequence and is mediated via a specific KP receptor (GPR-54). 6,7 Lack of KP signaling via the GPR-54 receptor is associated with reproductive system failure. 8 Cleavage of the KP 45−54 peptide between residues 51 and 52 by matrix metalloproteinases abolishes the activation of GPR-54 by the KP 45−54 peptide. 9 The KP 42−54 and KP 45−54 peptides also activate NPFF receptors, 10,11 and some of the actions of KP peptides could be mediated by NPFF receptor activation.There are profound changes in KP signaling at menopause 12 and notable sex differences in hypothalamic neurodegenera...

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mentioning

confidence: 99%

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

Milton

Chilumuri

Rocha‐Ferreira

et al. 2012

ACS Chem. Neurosci.

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“…Inactivating mutations of two of these, kisspeptin (KP) and neurokinin B (NKB), or their cognate receptors, recently highlighted the crucial role of these neuropeptides in GnRH neurone activation, as these mutations result in a failure to progress through puberty and in adult infertility [6][7][8][9][10][11] . In addition to these major modulators of GnRH secretion, neuropeptide Y, products of the pro-opiomelanocortin protein, gonadotropin-inhibitory-hormone (GnIH) and neurotransmitters such as gamma amino butyric acid and glutamine also regulate GnRH neurone activity 12,13 .…”

Section: B Sex Steroid-dependent Reproductive Diseasesmentioning

confidence: 99%

“…Physico-chemical studies utilising tryptophan fluorescence, conformational memory simulations, nuclear magnetic resonance and ion mobility mass spectrometry have indicated that mammalian GnRH assumes a folded confirmation around Gly 6 . This is depicted in the NMR structure in Figure 3.…”

Section: Gnrh Peptide Agonist and Antagonist Analoguesmentioning

confidence: 99%

“…In alanine scanning, each residue is systematically substituted with alanine which lacks a functional side chain, thus revealing whether the side chain is of importance or not. This approach revealed that alanine substitutions for Phe 6 and Phe 10 of KP-10 significantly reduced binding and activation of GPR54 in vitro and in vivo, indicating that aromatic side chains groups in amino acids in these positions are required for activity 107,108 .…”

Section: Kp Peptide Agonist and Antagonist Analoguesmentioning

confidence: 99%

“…This suggested the existence of steroid-responsive neurons which regulate GnRH neurons. A breakthrough in identifying such neurons occurred with the observation that inactivating mutations in genes encoding the human and mouse kisspeptin (KP) receptors (GPR54/Gpr54) resulted in a failure to progress through puberty 6,7 . An inactivating mutation in the human gene encoding KP (KiSS-1) also resulted in a failure to achieve puberty 8 .The discoveries that the KPs and their cognate receptor GPR54 play a key neuroendocrine role in the regulation of reproduction 7 is regarded as a milestone of equivalent importance to the discovery of GnRH more than three decades ago.…”

Section: Introductionmentioning

confidence: 99%

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Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Millar

Newton

2013

Nat Rev Endocrinol

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Reproductive hormones impact on all stages of life from gamete production, fertilisation, fetal development and parturition, neonatal development and puberty through to adulthood and senescence.The reproductive hormone cascade has therefore been the target for the development of numerous drugs which modulate its activity at many levels. As the central regulator of the cascade, gonadotropinreleasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent deseases such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilisation (IVF) protocols. Recently-discovered neuroendocrine peptides, kisspeptin (KP) and neurokinin B (NKB), have also been identified as therapeutic targets and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade, GnRH, KP and NKB.

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Effects of Kisspeptin on Sexual Brain Processing and Penile Tumescence in Men With Hypoactive Sexual Desire Disorder

et al. 2023

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ImportanceThe human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.ObjectiveTo determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.Design, Setting, and ParticipantsThis double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.InterventionsParticipants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.Main Outcomes and MeasuresChanges in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level–dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.ResultsOf the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire—most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02).Conclusions and RelevanceCollectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire.Trial Registrationisrctn.org Identifier: ISRCTN17271094

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Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54

Cited by 2,129 publications

References 36 publications

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Effects of Kisspeptin on Sexual Brain Processing and Penile Tumescence in Men With Hypoactive Sexual Desire Disorder

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