Characterization of the action of tachykinin signaling on pulsatile LH secretion in male mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Rajae Talbi ◽  
Ferrari Kaitlin ◽  
Ji Hae Choi ◽  
Achi Gerutshang ◽  
Elizabeth A McCarthy ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Neurokinin A ◽  
Male Mice ◽  
Intact Male ◽  
Stimulatory Action ◽  
The Individual ◽  
Lh Secretion ◽  
Increased Activity

Abstract The alternation of the stimulatory action of the tachykinin neurokinin B (NKB) and the inhibitory action of dynorphin within arcuate (ARH) Kiss1 neurons has been proposed as the mechanism behind the generation of GnRH pulses through the pulsatile release of kisspeptin. However, we have recently documented that GnRH pulses still exist in gonadectomized mice in the absence of tachykinin signaling. Here, we document an increase in basal frequency and amplitude of LH pulses in intact male mice deficient in substance P (SP), neurokinin A (NKA) signaling (Tac1KO) and NKB signaling (Tac2KO and Tacr3KO). Moreover, we offer evidence that a single bolus of the NKB receptor agonist senktide to gonad intact WT males increases the basal release of LH without changing its frequency. Altogether, these data support the dispensable role of the individual tachykinin systems in the generation of LH pulses. Moreover, the increased activity of the GnRH pulse generator in intact KO male mice suggests the existence of compensation by additional mechanisms in the generation of kisspeptin/GnRH pulses.

scholarly journals Neural Determinants of Pulsatile Luteinizing Hormone Secretion in Male Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (2) ◽  
Author(s):  
Su Young Han ◽  
Isaiah Cheong ◽  
Tim McLennan ◽  
Allan E Herbison
Keyword(s):  
Luteinizing Hormone ◽  
High Frequency ◽  
Pulse Generator ◽  
Hormone Secretion ◽  
Pulse Frequency ◽  
Male Mice ◽  
Intact Male ◽  
Luteinizing Hormone Secretion ◽  
Pulse Profile ◽  
Lh Secretion

Abstract The gonadotrophin-releasing hormone (GnRH) pulse generator drives pulsatile luteinizing hormone (LH) secretion essential for fertility. However, the constraints within which the pulse generator operates to drive efficient LH pulsatility remain unclear. We used optogenetic activation of the arcuate nucleus kisspeptin neurons, recently identified as the GnRH pulse generator, to assess the efficiency of different pulse generator frequencies in driving pulsatile LH secretion in intact freely behaving male mice. Activating the pulse generator at 45-minute intervals generated LH pulses similar to those observed in intact male mice while 9-minute interval stimulation generated LH profiles indistinguishable from gonadectomized (GDX) male mice. However, more frequent activation of the pulse generator resulted in disordered LH secretion. Optogenetic experiments directly activating the distal projections of the GnRH neuron gave the exact same results, indicating the pituitary to be the locus of the high frequency decoding. To evaluate the state-dependent behavior of the pulse generator, the effects of high-frequency activation of the arcuate kisspeptin neurons were compared in GDX and intact mice. The same stimulus resulted in an overall inhibition of LH release in GDX mice but stimulation in intact males. These studies demonstrate that the GnRH pulse generator is the primary determinant of LH pulse profile and that a nonlinear relationship exists between pulse generator frequency and LH pulse frequency. This may underlie the ability of stimulatory inputs to the pulse generator to have opposite effects on LH secretion in intact and GDX animals.

scholarly journals Characterization of the Role of NKA in the Control of Puberty Onset and Gonadotropin Release in the Female Mouse

Endocrinology ◽  
2019 ◽  
Vol 160 (10) ◽  
pp. 2453-2463 ◽  
Author(s):  
Silvia León ◽  
Chrysanthi Fergani ◽  
Rajae Talbi ◽  
Serap Simavli ◽  
Caroline A Maguire ◽  
...  
Keyword(s):  
Sex Steroids ◽  
Neurokinin A ◽  
Central Control ◽  
Gnrh Release ◽  
Lh Release ◽  
Timing Of Puberty ◽  
Puberty Onset ◽  
Lh Secretion

Abstract The tachykinin neurokinin B (NKB, Tac2) is critical for proper GnRH release in mammals, however, the role of the other tachykinins, such as substance P (SP) and neurokinin A (NKA) in reproduction, is still not well understood. In this study, we demonstrate that NKA controls the timing of puberty onset (similar to NKB and SP) and stimulates LH release in adulthood through NKB-independent (but kisspeptin-dependent) mechanisms in the presence of sex steroids. Furthermore, this is achieved, at least in part, through the autosynaptic activation of Tac1 neurons, which express NK2R (Tacr2), the receptor for NKA. Conversely, in the absence of sex steroids, as observed in ovariectomy, NKA inhibits LH through a mechanism that requires the presence of functional receptors for NKB and dynorphin (NK3R and KOR, respectively). Moreover, the ability of NKA to modulate LH secretion is absent in Kiss1KO mice, suggesting that its action occurs upstream of Kiss1 neurons. Overall, we demonstrate that NKA signaling is a critical component in the central control of reproduction, by contributing to the indirect regulation of kisspeptin release.

Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton

2018 ◽  
Vol 239 (3) ◽  
pp. 303-312 ◽  
Author(s):  
H H Farman ◽  
K L Gustafsson ◽  
P Henning ◽  
L Grahnemo ◽  
V Lionikaite ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Areal Bone Mineral Density ◽  
Male Mice ◽  
Mineral Density ◽  
Intact Male ◽  
Trabecular Thickness ◽  
Total Body

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

scholarly journals Regeneration: Why junk DNA might matter

2018 ◽  
Author(s):  
Carlos Díaz-Castillo
Keyword(s):  
Natural Variation ◽  
Spatial Organization ◽  
Natural Phenomena ◽  
Collective Knowledge ◽  
Junk Dna ◽  
Research Fields ◽  
Biological Variables ◽  
The Individual

The ability of certain natural species to restore or regenerate missing structures has been a recurrent source of inspiration to forge our collective knowledge, from being used to adorn mythological figures with superhuman powers to permitting controlled reproducible observations that help setting the bases of entire research fields such as experimental biology and regenerative medicine. In spite of being one of the oldest natural phenomena under study, what makes certain species able or unable to regenerate missing parts is still largely a mystery. Recent advancements towards the highly detailed characterization of the sequence, the spatial organization, and the expression of genomes is offering a new standpoint to address the study of the natural variation in regenerative responses. An intriguing observation that has not yet conveniently pursued is that species with remarkable regenerative abilities tend to have genomes loaded with junk DNA (jDNA), i.e., genetic elements presumed to be useless for the benefit of the individual, whereas species for taxa with limited regenerative abilities tend to have jDNA-poor genomes. Here, I use existing knowledge on the role of jDNA as genome evolution facilitator and its non-random chromosome and nuclear distributions to speculate about two non-excluding ways through which the variation in jDNA genomic content might end up enhancing or limiting regenerative responses. The present piece aims to go beyond the confines of correlational studies between biological variables and to lay sensible conceptual grounds for future hypothesis-driven attempts to substantiate the genomic determinants of the natural variation of regenerative responses.

scholarly journals Definition of the hypothalamic GnRH pulse generator in mice

2017 ◽  
Vol 114 (47) ◽  
pp. E10216-E10223 ◽  
Author(s):  
Jenny Clarkson ◽  
Su Young Han ◽  
Richard Piet ◽  
Timothy McLennan ◽  
Grace M. Kane ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Pulse Generator ◽  
Hormone Secretion ◽  
Pulse Generation ◽  
Neuron Population ◽  
Lh Pulsatility ◽  
Freely Behaving ◽  
Definition Of ◽  
Lh Secretion

The pulsatile release of luteinizing hormone (LH) is critical for mammalian fertility. However, despite several decades of investigation, the identity of the neuronal network generating pulsatile reproductive hormone secretion remains unproven. We use here a variety of optogenetic approaches in freely behaving mice to evaluate the role of the arcuate nucleus kisspeptin (ARNKISS) neurons in LH pulse generation. Using GCaMP6 fiber photometry, we find that the ARNKISS neuron population exhibits brief (∼1 min) synchronized episodes of calcium activity occurring as frequently as every 9 min in gonadectomized mice. These ARNKISS population events were found to be near-perfectly correlated with pulsatile LH secretion. The selective optogenetic activation of ARNKISS neurons for 1 min generated pulses of LH in freely behaving mice, whereas inhibition with archaerhodopsin for 30 min suppressed LH pulsatility. Experiments aimed at resetting the activity of the ARNKISS neuron population with halorhodopsin were found to reset ongoing LH pulsatility. These observations indicate the ARNKISS neurons as the long-elusive hypothalamic pulse generator driving fertility.

scholarly journals GTPase-Activating Proteins for Cdc42

2002 ◽  
Vol 1 (3) ◽  
pp. 469-480 ◽  
Author(s):  
Gregory R. Smith ◽  
Scott A. Givan ◽  
Paul Cullen ◽  
George F. Sprague
Keyword(s):  
Rho Gtpase ◽  
Invasive Growth ◽  
Gtpase Activating Proteins ◽  
Morphological Defects ◽  
P21 Activated Kinase ◽  
The Individual ◽  
Hydrolysis Of ◽  
Pak Kinase

ABSTRACT The Rho-type GTPase, Cdc42, has been implicated in a variety of functions in the yeast life cycle, including septin organization for cytokinesis, pheromone response, and haploid invasive growth. A group of proteins called GTPase-activating proteins (GAPs) catalyze the hydrolysis of GTP to GDP, thereby inactivating Cdc42. At the time this study began, there was one known GAP, Bem3, and one putative GAP, Rga1, for Cdc42. We identified another putative GAP for Cdc42 and named it Rga2 (Rho GTPase-activating protein 2). We confirmed by genetic and biochemical criteria that Rga1, Rga2, and Bem3 act as GAPs for Cdc42. A detailed characterization of Rga1, Rga2, and Bem3 suggested that they regulate different subsets of Cdc42 function. In particular, deletion of the individual GAPs conferred different phenotypes. For example, deletion of RGA1, but not RGA2 or BEM3, caused hyperinvasive growth. Furthermore, overproduction or loss of Rga1 and Rga2, but not Bem3, affected the two-hybrid interaction of Cdc42 with Ste20, a p21-activated kinase (PAK) kinase required for haploid invasive growth. These results suggest Rga1, and possibly Rga2, facilitate the interaction of Cdc42 with Ste20 to mediate signaling in the haploid invasive growth pathway. Deletion of BEM3 resulted in cells with severe morphological defects not observed in rga1Δ or rga2Δ strains. These data suggest that Bem3 and, to a lesser extent, Rga1 and Rga2 facilitate the role of Cdc42 in septin organization. Thus, it appears that the GAPs play a role in modulating specific aspects of Cdc42 function. Alternatively, the different phenotypes could reflect quantitative rather than qualitative differences in GAP activity in the mutant strains.

scholarly journals Anxiogenic and Stressor Effects of the Hypothalamic Neuropeptide RFRP-3 Are Overcome by the NPFFR Antagonist GJ14

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4152-4162 ◽  
Author(s):  
Joon S. Kim ◽  
Phil W. Brownjohn ◽  
Blake S. Dyer ◽  
Massimiliano Beltramo ◽  
Christopher S. Walker ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Stimulatory Action ◽  
Pharmacological Characterization ◽  
Neuropeptide Ff ◽  
Chronic Infusion ◽  
Corticosterone Release

RFamide-related peptide-3 (RFRP-3) is a recently discovered neuropeptide that has been proposed to play a role in the stress response. We aimed to elucidate the role of RFRP-3 and its receptor, neuropeptide FF (NPFF1R), in modulation of stress and anxiety responses. To achieve this, we characterized a new NPFF1R antagonist because our results showed that the only commercially available putative antagonist, RF9, is in fact an agonist at both NPFF1R and the kisspeptin receptor (KISS1R). We report here the identification and pharmacological characterization of GJ14, a true NPFFR antagonist. In in vivo tests of hypothalamic-pituitary-adrenal (HPA) axis function, GJ14 completely blocked RFRP-3-induced corticosterone release and neuronal activation in CRH neurons. Furthermore, chronic infusion of GJ14 led to anxiolytic-like behavior, whereas RFRP-3 infusion had anxiogenic effects. Mice receiving chronic RFRP-3 infusion also had higher basal circulating corticosterone levels. These results indicate a stimulatory action of RFRP-3 on the HPA axis, consistent with the dense expression of NPFF1R in the vicinity of CRH neurons. Importantly, coinfusion of RFRP-3 and GJ14 completely reversed the anxiogenic and HPA axis-stimulatory effects of RFRP-3. Here we have established the role of RFRP-3 as a regulator of stress and anxiety. We also show that GJ14 can reverse the effects of RFRP-3 both in vitro and in vivo. Infusion of GJ14 causes anxiolysis, revealing a novel potential target for treating anxiety disorders.

scholarly journals The Role of the Medial and Central Amygdala in Stress-Induced Suppression of Pulsatile LH Secretion in Female Rats

Endocrinology ◽  
2011 ◽  
Vol 152 (2) ◽  
pp. 545-555 ◽  
Author(s):  
Yuanshao Lin ◽  
Xiaofeng Li ◽  
Micol Lupi ◽  
James S. Kinsey-Jones ◽  
Bei Shao ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Reproductive Function ◽  
Ibotenic Acid ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Inhibitory Effects ◽  
Cardiac Catheters ◽  
Response To Stress ◽  
Lh Secretion

Abstract Stress exerts profound inhibitory effects on reproductive function by suppressing the pulsatile release of GnRH and therefore LH. Although the mechanisms by which stressors disrupt the hypothalamic GnRH pulse generator remain to be fully elucidated, numerous studies have implicated the amygdala, especially its medial (MeA) and central nuclei (CeA), as key modulators of the neuroendocrine response to stress. In the present study, we investigated the roles of the MeA and CeA in stress-induced suppression of LH pulses. Ovariectomized rats received bilateral ibotenic acid or sham lesions targeting the MeA or CeA; blood samples (25 μl) were taken via chronically implanted cardiac catheters every 5 min for 6 h for the measurement of LH pulses. After 2 h of baseline sampling, the rats were exposed to either: restraint (1 h), insulin-induced hypoglycemia (IIH) (0.3 U/kg, iv), or lipopolysaccharide (LPS) (25 μg/kg, iv) stress. The restraint but not IIH or LPS stress–induced suppression of LH pulses was markedly attenuated by the MeA lesions. In contrast, CeA lesioning attenuated LPS, but not restraint or IIH stress–induced suppression of LH pulses. Moreover, after restraint stress, the number of Fos-positive neurons and the percentage of glutamic acid decarboxylase67 neurons expressing Fos was significantly greater in the GnRH-rich medial preoptic area (mPOA) of rats with intact, rather than lesioned, MeA. These data indicate that the MeA and CeA play key roles in psychogenic and immunological stress-induced suppression of the GnRH pulse generator, respectively, and the MeA-mediated effect may involve γ-aminobutyric acid ergic signaling within the mPOA.

Extragonadal effects of luteinizing hormone in mice

1989 ◽  
Vol 121 (4) ◽  
pp. 587-594 ◽  
Author(s):  
Kaoru Nomura ◽  
David W. Puett ◽  
David Puett ◽  
Kazuo Shizume ◽  
Grant W. Liddle
Keyword(s):  
Physiological Role ◽  
Male Mice ◽  
Intact Female ◽  
Intact Male ◽  
Kidney Weight ◽  
Kidney Size ◽  
Female Mice ◽  
Cellular Hypertrophy ◽  
Kidney Growth

Abstract. LH is composed of isoforms which exhibit microheterogeneity. We recently demonstrated that a particular ovine or porcine LH preparation (G100-fr.3) stimulates kidney growth. This study was conducted to clarify the physiological role of this renotropic activity and other extragonadal effects of the ovine LH preparation in CD-1 mice. Hypophysectomy caused a significantly greater reduction in relative dry kidney weight (i.e. g/100 g body weight) when compared to adrenalectomy, castration, thyroidectomy, and castration plus thyroidectomy. Supplementation with G100-fr.3 in these animals partially restored not only kidney size but also DNA, RNA and protein content. Treatment with standard LH preparations (NIDDKoLH24 and G3-268DA), as well as PRL, GH, FSH and TSH, failed to reverse the renal atrophy induced by hypophysectomy and castration. Administration of testosterone to castrated hypophysectomized mice increased kidney weight and RNA content, but not renal DNA. The relative dry kidney weight increased significantly at the onset of puberty in intact male mice, but not in castrated males or intact female mice. In addition, human CG increased kidney size in hypophysectomized male mice, but not in castrated hypophysectomized animals. These findings indicate that LH isoforms may regulate kidney growth in the male mouse both directly as a renotropin stimulating hyperplasia and indirectly as a gonadotropin via testicular androgen, producing cellular hypertrophy. It was also noted that G100-fr.3 decreased hepatic weight, DNA, RNA and protein, but produced no significant change in the spleen, heart or adrenal glands in castrated-hypophysectomized mice. Such extragonadal effects of G100-fr.3 were also observed in intact female mice. These results suggest that certain LH isoforms may have extragonadal actions involving the kidney and liver.

scholarly journals Structural Basis of Subtilase Cytotoxin SubAB Assembly

2013 ◽  
Vol 288 (38) ◽  
pp. 27505-27516 ◽  
Author(s):  
Jérôme Le Nours ◽  
Adrienne W. Paton ◽  
Emma Byres ◽  
Sally Troy ◽  
Brock P. Herdman ◽  
...  
Keyword(s):  
Dominant Role ◽  
Functional Characterization ◽  
Structural Basis ◽  
Sequence Comparisons ◽  
A Subunit ◽  
The Individual ◽  
A1 Domain ◽  
Cellular Dysfunction

Pathogenic strains of Escherichia coli produce a number of toxins that belong to the AB5 toxin family, which comprise a catalytic A-subunit that induces cellular dysfunction and a B-pentamer that recognizes host glycans. Although the molecular actions of many of the individual subunits of AB5 toxins are well understood, how they self-associate and the effect of this association on cytotoxicity are poorly understood. Here we have solved the structure of the holo-SubAB toxin that, in contrast to other AB5 toxins whose molecular targets are located in the cytosol, cleaves the endoplasmic reticulum chaperone BiP. SubA interacts with SubB in a similar manner to other AB5 toxins via the A2 helix and a conserved disulfide bond that joins the A1 domain with the A2 helix. The structure revealed that the active site of SubA is not occluded by the B-pentamer, and the B-pentamer does not enhance or inhibit the activity of SubA. Structure-based sequence comparisons with other AB5 toxin family members, combined with extensive mutagenesis studies on SubB, show how the hydrophobic patch on top of the B-pentamer plays a dominant role in binding the A-subunit. The structure of SubAB and the accompanying functional characterization of various mutants of SubAB provide a framework for understanding the important role of the B-pentamer in the assembly and the intracellular trafficking of this AB5 toxin.

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