Unraveling the connection between GABA and Kisspeptin in the control of reproduction (original) (raw)
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The Journal of Neuroscience
A population of kisspeptin-GABA coexpressing neurons located in the rostral periventricular area of the third ventricle (RP3V) is believed to activate gonadotropin-releasing hormone (GnRH) neurons to generate the luteinizing hormone (LH) surge triggering ovulation. Selective optogenetic activation of RP3V kisspeptin (RP3V KISS) neurons in female mice for Ͼ30 s and Ն10 Hz in either a continuous or bursting mode was found to reliably generate a delayed and long-lasting activation of GnRH neuron firing in brain slices. Optogenetic activation of RP3V KISS neurons in vivo at 10 Hz generated substantial increments in LH secretion of similar amplitude to the endogenous LH surge. Studies using GABA A receptor antagonists and optogenetic activation of RP3V GABA (RP3V GABA) neurons in vitro revealed that low-frequency (2 Hz) stimulation generated immediate and transient GABA A receptor-mediated increases in GnRH neuron firing, whereas higher frequencies (10 Hz) recruited the long-lasting activation observed following RP3V KISS neuron stimulation. In vivo, 2 Hz activation of RP3V GABA neurons did not alter LH secretion, whereas 10 Hz stimulation evoked a sustained large increase in LH identical to RP3V KISS neuron activation. Optogenetic activation of RP3V KISS neurons in which kisspeptin had been deleted did not alter LH secretion. These studies demonstrate the presence of parallel transmission streams from RP3V neurons to GnRH neurons that are frequency dependent and temporally distinct. This comprises a rapid and transient GABA A receptor-mediated activation and a slower onset kisspeptin-mediated stimulation of long duration. At the time of the LH surge, GABA release appears to be functionally redundant with the neuropeptide kisspeptin being the dominant cotransmitter influencing GnRH neuron output.
The role of kisspeptin neuropeptide in controlling reproduction
INDIAN JOURNAL OF ANIMAL HEALTH
The pulsatile release of gonadotrophin-releasing hormone (GnRH) from the hypothalamus serves as the ultimate output signal for the regulation of reproductive processes, which integrate a number of elements from both the internal and external environment. A potent endogenous secretagogue of GnRH, kisspeptin, is produced by hypothalamic neurons. Kisspeptin has physiological relevance and a variety of reproductive functions. It controls both the pulsatile GnRH secretion that drives folliculogenesis, spermatogenesis, and steroidogenesis as well as the GnRH surge that causes ovulation in females. It plays a crucial role in the central regulation of the timing of puberty onset and reproduction in animals. Kisspeptin and related substances could therefore be valuable for the development of novel strategies for the management of fertility in farm animals and are now universally recognized as a key player in the control of critical aspects of reproductive development and function from sexual differentiation to regulation of GnRH /gonadotropin secretion.
Journal of chemical neuroanatomy, 2018
Reproductive function is regulated by the hypothalamic-pituitary-gonads (HPG) axis. Hypothalamic neurons synthesizing kisspeptin play a fundamental role in the central regulation of the timing of puberty onset and reproduction in mammals. Kisspeptin is a regulator of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH). In female rodent, the kisspeptin (encoded by kiss1 gene), neurokinin B (Tac3) and dynorphin neurons form the basis for the "KNDy neurons" in the arcuate nucleus and play a fundamental role in the regulation of GnRH/LH release. Furthermore, various factors including neurotransmitters and neuropeptides may cooperate with kisspeptin signaling to modulate GnRH function. Many neuropeptides including proopiomelanocortin, neuropeptide Y, agouti-related protein, and other neuropeptides, as well as neurotransmitters, dopamine, norepinephrine and γ-aminobutyric acid are suggested to control feeding and HPG axis, the underlying mechanisms are not well kn...
Journal of Neuroendocrinology, 2000
Gonadotropin-releasing hormone (GnRH) is the primary hypothalamic factor responsible for the control of gonadotropin secretion in vertebrates. However, within the last decade, two other hypothalamic neuropeptides have been found to play key roles in the control of reproductive functions: gonadotropin-inhibitory hormone (GnIH) and kisspeptin. In 2000, we discovered GnIH in the quail hypothalamus. GnIH inhibits gonadotropin synthesis and release in birds through actions on GnRH neurons and gonadotropes, mediated via GPR147. Subsequently, GnIH orthologs were identified in other vertebrate species from fish to humans. As in birds, mammalian and fish GnIH orthologs inhibit gonadotropin release, indicating a conserved role for this neuropeptide in the control of the hypothalamo-pituitary-gonadal (HPG) axis across species. Following the discovery of GnIH, kisspeptin, encoded by the KiSS-1 gene, was discovered in mammals. In contrast to GnIH, kisspeptin has a direct stimulatory effect on GnRH neurons via GPR54. GPR54 is also expressed in pituitary cells, but whether gonadotropes are targets for kisspeptin remains unresolved. The KiSS-1 gene is also highly conserved and has been identified in mammals, amphibians and fish. We have recently found a second isoform of KiSS-1, designated KiSS-2, in several vertebrates, but not birds, rodents or primates. In this review, we highlight the discovery, mechanisms of action, and functional significance of these two chief regulators of the reproductive axis.
Kisspeptins and GnRH neuronal signalling
Trends in Endocrinology & Metabolism, 2009
Kisspeptin binding to its G-protein-coupled receptor KISS1R (also known as GPR54), which is expressed by gonadotropin-releasing hormone (GnRH) neurons, stimulates GnRH release and activation of the mammalian reproductive axis. Kisspeptin neurons make close contact with GnRH neurons acting at both the cell body and the nerve terminals. Kisspeptin can act directly on GnRH neurons and/or indirectly via synaptic input from other neurons to inhibit inwardly rectifying potassium channels and activate non-specific cation channels, with the effect of long-lasting depolarization and increased action potential firing rate. This review covers the recent advances in the molecular consequences of kisspeptin action on GnRH neurons and how these neuronal circuits are integrated in different species. These studies provide insight into the mechanism by which kisspeptin regulates the reproductive axis.
Kisspeptins in Reproductive Biology: Consensus Knowledge and Recent Developments
Biology of Reproduction, 2011
Kisspeptins, a family of neuropeptides encoded by the Kiss1 gene that are mainly expressed in discrete neuronal populations of the hypothalamus, have recently emerged as essential upstream regulatory elements of GnRH (gonadotropin-releasing hormone) neurons and, thereby, potent elicitors of gonadotropin secretion. Indeed, kisspeptins are now recognized as important regulators of key aspects of the maturation and function of the reproductive axis, including the sexual differentiation of the brain, the timing of puberty, the adult regulation of gonadotropin secretion by gonadal hormones, and the control of fertility by metabolic and environmental (e.g., photoperiod) cues. Appreciation of these fundamental biological features has led to the contention that kisspeptins are indispensable elements of the reproductive brain whose relevance goes beyond their crucial physiological roles and may pose potential pathophysiological and therapeutic interest. In spite of such a consensus, recent developments in the field have helped to expand, and somewhat challenged, our current understanding of the neuroendocrine and molecular mechanisms whereby some of the effects of kisspeptins are conducted. This review aims to provide a synoptic and balanced account of the consensus knowledge and recent findings in the field of kisspeptin physiology, which we predict will be crucial in shaping the progress of our understanding of the roles played by this family of neuropeptides in reproductive biology.
Proceedings of the National Academy of Sciences, 2005
We have recently described a molecular gatekeeper of the hypothalamic-pituitary-gonadal axis with the observation that G protein-coupled receptor 54 (GPR54) is required in mice and men for the pubertal onset of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion to occur. In the present study, we investigate the possible central mode of action of GPR54 and kisspeptin ligand. First, we show that GPR54 transcripts are colocalized with gonadotropin-releasing hormone (GnRH) neurons in the mouse hypothalamus, suggesting that kisspeptin, the GPR54 ligand, may act directly on these neurons. Next, we show that GnRH neurons seem anatomically normal in gpr54 ؊/؊ mice, and that they show projections to the median eminence, which demonstrates that the hypogonadism in gpr54 ؊/؊ mice is not due to an abnormal migration of GnRH neurons (as occurs with KAL1 mutations), but that it is more likely due to a lack of GnRH release or absence of GnRH neuron stimulation. We also show that levels of kisspeptin injected i.p., which stimulate robust LH and FSH release in wild-type mice, have no effect in gpr54 ؊/؊ mice, and therefore that kisspeptin acts directly and uniquely by means of GPR54 signaling for this function. Finally, we demonstrate by direct measurement, that the central administration of kisspeptin intracerebroventricularly in sheep produces a dramatic release of GnRH into the cerebrospinal fluid, with a parallel rise in serum LH, demonstrating that a key action of kisspeptin on the hypothalamo-pituitary-gonadal axis occurs directly at the level of GnRH release. The localization and GnRH release effects of kisspeptin thus define GPR54 as a major control point in the reproductive axis and suggest kisspeptin to be a neurohormonal effector.
Kisspeptin increases GnRH mRNA expression and secretion in GnRH secreting neuronal cell lines
Molecular and cellular endocrinology, 2009
Kisspeptins, and their G-protein coupled receptor 54 (GPR54), are key components in the regulation of gonadotropin-releasing hormone (GnRH) secretion in humans and other mammals. Several studies demonstrate that the central or systemic administration of kisspeptin increases GnRH and gonadotropin secretion in both prepubertal and adult animals; however, the cellular targets and intracellular mechanisms of action in the central reproductive axis are unclear. In this study, we documented the presence of GPR54 in two GnRH secreting neuronal cell lines (GT1-7 and GN11). Kisspeptin treatment increases GnRH secretion and GnRH mRNA levels in a dose and time dependent manner. 10(-9)M kisspeptin maximally stimulated GnRH secretion by 2-fold and GnRH mRNA levels up to 4-fold after 4h of treatment in both cell lines. Negative regulation by 17beta-estradiol of GnRH secretion and GnRH mRNA was antagonized by kisspeptin. Co-treatment with kisspeptin and 17beta-estradiol increased GnRH secretion by...
The Iranian Journal of Veterinary Science and Technology, 2021
Kisspeptin stimulates gonadotropin releasing hormone (GnRH). The GnRH neurons receive inhibitory inputs from ghrelin, RFamide related peptide-3 (RFRP-3), and gamma-aminobutyric acid (GABA) neurons. Polycystic ovary syndrome (PCOS) is associated with increased levels of GnRH/LH and kisspeptin, and decreased release of GABA, ghrelin, and RFRP-3. In the present study, the effects of GABAB receptor agonist, baclofen, were investigated on GnRH, KiSS1, RFRP-3, and ghrelin gene expression in the hypothalamus of PCOS model rats. For induction of PCOS, female Wistar rats weighing 180-200g received intra-muscular injection of estradiol valerate. Fifteen PCOS rats in three groups received intraperitoneal injections of saline, 5, or 10 mg/kg baclofen for two weeks. The hypothalamic samples were dissected. Gene expression levels of GnRH, KiSS1, RFRP-3, and ghrelin were determined by real time qPCR method. Results revealed that baclofen significantly decreased the mean relative KiSS1 gene expres...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2016
Gonadotropin-inhibitory hormone (GnIH) acts as a negative regulator of reproduction by acting on gonadotropes and gonadotropin-releasing hormone (GnRH) neurons. Despite its functional significance, the molecular mechanism of GnIH action in the target cells has not been fully elucidated. To expand our previous study on GnIH actions in gonadotropes, we investigated the potential signal transduction pathway that conveys the inhibitory action of GnIH in GnRH neurons by using the GnRH neuronal cell line, GT1-7. We examined whether GnIH inhibits the action of kisspeptin and vasoactive intestinal polypeptide (VIP), positive regulators of GnRH neurons. Although GnIH significantly suppressed the stimulatory effect of kisspeptin on GnRH release in hypothalamic culture, GnIH had no inhibitory effect on kisspeptin stimulation of serum response element and nuclear factor of activated T-cells response element activities and ERK phosphorylation, indicating that GnIH may not directly inhibit kisspe...