scholarly journals Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling

Reproduction ◽  
2006 ◽  
Vol 131 (4) ◽  
pp. 623-630 ◽  
Author(s):  
Jeremy T Smith ◽  
Donald K Clifton ◽  
Robert A Steiner
Keyword(s):  
Sex Steroids ◽  
Arcuate Nucleus ◽  
Direct Action ◽  
Hypogonadotropic Hypogonadism ◽  
Feedback Regulation ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Reproductive Axis ◽  
G Protein Coupled ◽  
The Brain

The Kiss1 gene codes for a family of peptides that act as endogenous ligands for the G protein-coupled receptor GPR54. Spontaneous mutations or targeted deletions of GPR54 in man and mice produce hypogonadotropic hypogonadism and infertility. Centrally administered kisspeptins stimulate gonadotropin secretion by acting directly on GnRH neurons. Sex steroids regulate the expression of KiSS-1 mRNA in the brain through direct action on KiSS-1 neurons. In the arcuate nucleus (Arc), sex steroids inhibit the expression of KiSS-1, suggesting that these neurons serve as a conduit for the negative feedback regulation of gonadotropin secretion. In the anteroventral periventricular nucleus (AVPV), sex steroids induce the expression of KiSS-1, implying that KiSS-1 neurons in this region may have a role in the preovulatory LH surge (in the female) or sexual behavior (in the male).

scholarly journals Minireview: Kisspeptin Neurons as Central Processors in the Regulation of Gonadotropin-Releasing Hormone Secretion

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1154-1158 ◽  
Author(s):  
Heather M. Dungan ◽  
Donald K Clifton ◽  
Robert A. Steiner
Keyword(s):  
Adult Animal ◽  
Mammalian Species ◽  
Hypogonadotropic Hypogonadism ◽  
Hormone Secretion ◽  
Feedback Regulation ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Gonadotropin Surge ◽  
G Protein Coupled ◽  
The Brain

The Kiss1 gene encodes a family of peptides called kisspeptins, which bind to the G protein-coupled receptor GPR54. Kisspeptin(s) and its receptor are expressed in the forebrain, and the discovery that mice and humans lacking a functional GPR54 fail to undergo puberty and exhibit hypogonadotropic hypogonadism implies that kisspeptin signaling plays an essential role in reproduction. Studies in several mammalian species have shown that kisspeptins stimulate the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain after the activation of GPR54, which is expressed by GnRH neurons. Kisspeptin is expressed abundantly in the arcuate nucleus (Arc) and the anteroventral periventricular nucleus (AVPV) of the forebrain. Both estradiol and testosterone regulate the expression of the Kiss1 gene in the Arc and AVPV; however, the response of the Kiss1 gene to these steroids is exactly opposite between these two nuclei. Estradiol and testosterone down-regulate Kiss1 mRNA in the Arc and up-regulate its expression in the AVPV. Thus, kisspeptin neurons in the Arc may participate in the negative feedback regulation of gonadotropin secretion, whereas kisspeptin neurons in the AVPV may contribute to generating the preovulatory gonadotropin surge in the female. Hypothalamic levels of Kiss1 and GPR54 mRNA increase dramatically at puberty, suggesting that kisspeptin signaling could mediate the neuroendocrine events that trigger the onset of puberty. Together, these observations demonstrate that kisspeptin-GPR54 signaling in the brain serves as an important conduit for controlling GnRH secretion in the developing and adult animal.

scholarly journals Regulation of Kiss1 Gene Expression in the Brain of the Female Mouse

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 3686-3692 ◽  
Author(s):  
Jeremy T. Smith ◽  
Matthew J. Cunningham ◽  
Emilie F. Rissman ◽  
Donald K Clifton ◽  
Robert A. Steiner
Keyword(s):  
Female Mouse ◽  
Arcuate Nucleus ◽  
Feedback Regulation ◽  
Wild Type ◽  
Negative Feedback Regulation ◽  
Gnrh Secretion ◽  
Double Label ◽  
G Protein Coupled ◽  
The Brain

The Kiss1 gene encodes a family of neuropeptides called kisspeptins, which activate the receptor G protein-coupled receptor-54 and play a role in the neuroendocrine regulation of GnRH secretion. We examined whether estradiol (E2) regulates KiSS-1 in the forebrain of the female mouse by comparing KiSS-1 mRNA expression among groups of ovary-intact (diestrus), ovariectomized (OVX), and OVX plus E2-treated mice. In the arcuate nucleus (Arc), KiSS-1 expression increased after ovariectomy and decreased with E2 treatment. Conversely, in the anteroventral periventricular nucleus (AVPV), KiSS-1 expression was reduced after ovariectomy and increased with E2 treatment. To determine whether the effects of E2 on KiSS-1 are mediated through estrogen receptor (ER)α or ERβ, we evaluated the effects of E2 in OVX mice that lacked functional ERα or ERβ. In OVX mice that lacked functional ERα, KiSS-1 mRNA did not respond to E2 in either the Arc or AVPV, suggesting that ERα is essential for mediating the inhibitory and stimulatory effects of E2. In contrast, KiSS-1 mRNA in OVX mice that lacked functional ERβ responded to E2 exactly as wild-type animals. Double-label in situ hybridization revealed that virtually all KiSS-1-expressing neurons in the Arc and AVPV coexpress ERα, suggesting that the effects of E2 are mediated directly through KiSS-1 neurons. We conclude that KiSS-1 neurons in the Arc, which are inhibited by E2, may play a role in the negative feedback regulation of GnRH secretion, whereas KiSS-1 neurons in the AVPV, which are stimulated by E2, may participate in the positive feedback regulation of GnRH secretion.

scholarly journals Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4265-4275 ◽  
Author(s):  
V. M. Navarro ◽  
M. L. Gottsch ◽  
M. Wu ◽  
D. García-Galiano ◽  
S. J. Hobbs ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Male Mouse ◽  
Arcuate Nucleus ◽  
Feedback Regulation ◽  
Dynorphin A ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Gnrh Neurons ◽  
Kndy Neurons ◽  
Lh Secretion

Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.

scholarly journals A Role for Kisspeptins in the Regulation of Gonadotropin Secretion in the Mouse

Endocrinology ◽  
2004 ◽  
Vol 145 (9) ◽  
pp. 4073-4077 ◽  
Author(s):  
M. L. Gottsch ◽  
M. J. Cunningham ◽  
J. T. Smith ◽  
S. M. Popa ◽  
B. V. Acohido ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Functional Anatomy ◽  
Biologically Active ◽  
Gonadotropin Secretion ◽  
Periventricular Nucleus ◽  
Lh Secretion ◽  
G Protein Coupled ◽  
The Brain ◽  
Gpr54 Gene

Abstract Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.

Development of gonadal feedback regulation of gonadotropin gene expression and secretion in female rats

1992 ◽  
Vol 127 (5) ◽  
pp. 454-458 ◽  
Author(s):  
Pirjo A Pakarinen ◽  
Ilpo T Huhtaniemi
Keyword(s):  
Negative Feedback ◽  
Feedback Regulation ◽  
Female Rats ◽  
Mrna Levels ◽  
Neonatal Rats ◽  
Adult Rats ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Pituitary Gonadotropin ◽  
Old Adult

The postnatal development of the gonadal negative feedback control of gonadotropins was studied in female rats. Neonatal (5-day-old) and randomly cycling young (60-day-old) and more mature (180-day-old) adult rats were ovariectomized, and half of them received Silastic implants containing the synthetic estrogen, diethylstilbestrol. The neonatal rats were killed 5, 10 or 15 days, and the adult rats 7 days after the operation. Age-matched and sham-operated animals served as controls. There were no statistically significant responses of serum LH or FSH concentrations or of the pituitary gonadotropin subunit mRNA levels to ovariectomy at any of the neonatal ages. A marked increase (p<0.01) after ovariectomy was seen in serum gonadotropins and in the cognate mRNA levels at both adult ages. In spite of the weak feedback response of the neonatal rats to ovariectomy, diethylstilbestrol suppressed the basal pituitary gonadotropin concentrations and the specific LH and FSH β-chain mRNAs (p<0.01–0.05). These results demonstrate that the gonadal negative feedback regulation of gonadotropin synthesis and secretion is not fully developed in neonatal and prepubertal female rats before 20 days of age. This is probably due to the steroidogenic quiescence of the ovaries in early life. However, the capability of the pituitary to respond to negative estrogen feedback has developed in the neonatal female, as demonstrated by the suppressive effects of diethylstilbestrol treatment on gonadotropin secretion.

scholarly journals Mechanisms of cross-talk between G-protein-coupled receptors resulting in enhanced release of intracellular Ca2+

2003 ◽  
Vol 374 (2) ◽  
pp. 281-296 ◽  
Author(s):  
Tim D. WERRY ◽  
Graeme F. WILKINSON ◽  
Gary B. WILLARS
Keyword(s):  
G Protein ◽  
Cross Talk ◽  
Cell Function ◽  
Feedback Regulation ◽  
G Protein Coupled Receptors ◽  
Negative Feedback Regulation ◽  
Cellular Processes ◽  
Heterologous Desensitization ◽  
G Protein Coupled

Alteration in [Ca2+]i (the intracellular concentration of Ca2+) is a key regulator of many cellular processes. To allow precise regulation of [Ca2+]i and a diversity of signalling by this ion, cells possess many mechanisms by which they are able to control [Ca2+]i both globally and at the subcellular level. Among these are many members of the superfamily of GPCRs (G-protein-coupled receptors), which are characterized by the presence of seven transmembrane domains. Typically, those receptors able to activate PLC (phospholipase C) enzymes cause release of Ca2+ from intracellular stores and influence Ca2+ entry across the plasma membrane. It has been well documented that Ca2+ signalling by one type of GPCR can be influenced by stimulation of a different type of GPCR. Indeed, many studies have demonstrated heterologous desensitization between two different PLC-coupled GPCRs. This is not surprising, given our current understanding of negative-feedback regulation and the likely shared components of the signalling pathway. However, there are also many documented examples of interactions between GPCRs, often coupling preferentially to different signalling pathways, which result in a potentiation of Ca2+ signalling. Such interactions have important implications for both the control of cell function and the interpretation of in vitro cell-based assays. However, there is currently no single mechanism that adequately accounts for all examples of this type of cross-talk. Indeed, many studies either have not addressed this issue or have been unable to determine the mechanism(s) involved. This review seeks to explore a range of possible mechanisms to convey their potential diversity and to provide a basis for further experimental investigation.

scholarly journals Neuropeptides as Primary Mediators of Brain Circuit Connectivity

2021 ◽  
Vol 15 ◽  
Author(s):  
Mathilde C. C. Guillaumin ◽  
Denis Burdakov
Keyword(s):  
Neural Circuit ◽  
Direct Action ◽  
Temporal Integration ◽  
Neuronal Membrane ◽  
Brain Functions ◽  
Neuronal Interactions ◽  
Evolutionarily Conserved ◽  
Neuronal Processing ◽  
G Protein Coupled ◽  
The Brain

Across sleep and wakefulness, brain function requires inter-neuronal interactions lasting beyond seconds. Yet, most studies of neural circuit connectivity focus on millisecond-scale interactions mediated by the classic fast transmitters, GABA and glutamate. In contrast, neural circuit roles of the largest transmitter family in the brain–the slow-acting peptide transmitters–remain relatively overlooked, or described as “modulatory.” Neuropeptides may efficiently implement sustained neural circuit connectivity, since they are not rapidly removed from the extracellular space, and their prolonged action does not require continuous presynaptic firing. From this perspective, we review actions of evolutionarily-conserved neuropeptides made by brain-wide-projecting hypothalamic neurons, focusing on lateral hypothalamus (LH) neuropeptides essential for stable consciousness: the orexins/hypocretins. Action potential-dependent orexin release inside and outside the hypothalamus evokes slow postsynaptic excitation. This excitation does not arise from modulation of classic neurotransmission, but involves direct action of orexins on their specific G-protein coupled receptors (GPCRs) coupled to ion channels. While millisecond-scale, GABA/glutamate connectivity within the LH may not be strong, re-assessing LH microcircuits from the peptidergic viewpoint is consistent with slow local microcircuits. The sustained actions of neuropeptides on neuronal membrane potential may enable core brain functions, such as temporal integration and the creation of lasting permissive signals that act as “eligibility traces” for context-dependent information routing and plasticity. The slowness of neuropeptides has unique advantages for efficient neuronal processing and feedback control of consciousness.

Interpretation of Serum Gonadotropin Levels in Hyperprolactinaemia

2018 ◽  
Vol 107 (2) ◽  
pp. 105-113 ◽  
Author(s):  
Ali Abbara ◽  
Sophie A. Clarke ◽  
Alexander Nesbitt ◽  
Sabreen Ali ◽  
Alexander N. Comninos ◽  
...  
Keyword(s):  
Prolactin Level ◽  
Hypogonadotropic Hypogonadism ◽  
Elevated Serum ◽  
Serum Levels ◽  
Serum Prolactin ◽  
Drug Induced ◽  
Gonadotropin Secretion ◽  
Reproductive Axis ◽  
Reproductive Endocrine ◽  
Serum Gonadotropin

Background/Aims: Hyperprolactinaemia is a common cause of amenorrhoea due to hypogonadotropic hypogonadism. Prolactin is hypothesised to impede the reproductive axis through an inhibitory action at the hypothalamus. However, limited data exist to aid the interpretation of serum gonadotropins in the context of hyperprolactinaemia. Methods: Serum gonadotropin values were reviewed in 243 patients with elevated serum monomeric prolactin due to discrete aetiologies at a tertiary reproductive endocrine centre between 2012 and 2015. The cause of hyperprolactinaemia was categorised by an experienced endocrinologist/pituitary multidisciplinary team, unless superseded by histology. The most frequently encountered diagnoses were microprolactinoma (n = 88), macroprolactinoma (n = 46), non-functioning pituitary adenoma (NFPA) (n = 72), drug-induced hyperprolactinaemia (n = 22) and polycystic ovarian syndrome (PCOS) (n = 15). Results: In patients with prolactinoma and modestly raised serum prolactin levels (< 4,000 mU/L), increasingly FSH-predominant gonadotropin values were observed with rising prolactin level, consistent with a progressive reduction in hypothalamic gonadotropin-releasing hormone (GnRH) pulsatility. Patients with prolactinoma and higher prolactin values (> 4,000 mU/L) were more likely to have a reduction in serum levels of both FSH and LH, consistent with direct pituitary gonadotrope dysfunction. Patients with macroadenoma and extremes of serum gonadotropin values (either serum FSH or LH > 8 IU/L) were more likely to have NFPA than prolactinoma. Patients with PCOS and hyperprolactinaemia had LH-predominant secretion in keeping with increased GnRH pulsatility despite a raised prolactin level. Conclusion: The pattern of gonadotropin secretion in patients with hyperprolactinaemia reflects the underlying aetiology.

scholarly journals Hypothalamic pathways linking energy balance and reproduction

2008 ◽  
Vol 294 (5) ◽  
pp. E827-E832 ◽  
Author(s):  
Jennifer W. Hill ◽  
Joel K. Elmquist ◽  
Carol F. Elias
Keyword(s):  
Energy Balance ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Arcuate Nucleus ◽  
Metabolic Stress ◽  
Reproductive Function ◽  
Reproductive Axis ◽  
Hypothalamic Nuclei ◽  
Adiposity Signals ◽  
The Brain

During periods of metabolic stress, animals must channel energy toward survival and away from processes such as reproduction. The reproductive axis, therefore, has the capacity to respond to changing levels of metabolic cues. The cellular and molecular mechanisms that link energy balance and reproduction, as well as the brain sites mediating this function, are still not well understood. This review focuses on the best characterized of the adiposity signals: leptin and insulin. We examine their reproductive role acting on the classic metabolic pathways of the arcuate nucleus, NPY/AgRP and POMC/CART neurons, and the newly identified kisspeptin network. In addition, other hypothalamic nuclei that may play a role in linking metabolic state and reproductive function are discussed. The nature of the interplay between these elements of the metabolic and reproductive systems presents a fascinating puzzle, whose pieces are just beginning to fall into place.

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