scholarly journals Sex Differences in Dopamine Receptor Signaling in Fmr1 Knockout Mice: A Pilot Study

2021 ◽  
Vol 11 (11) ◽  
pp. 1398
Author(s):  
Anlong Jiang ◽  
Le Wang ◽  
Justin Y. D. Lu ◽  
Amy Freeman ◽  
Charlie Campbell ◽  
...  
Keyword(s):  
Sex Differences ◽  
Glycogen Synthase ◽  
Genetic Disorder ◽  
D2 Receptor ◽  
D1 Receptor ◽  
Variable Degree ◽  
Wild Type ◽  
Female Mice ◽  
Dopamine Signaling ◽  
Gsk 3Β

Fragile X syndrome (FXS) is an X-chromosome-linked dominant genetic disorder that causes a variable degree of cognitive dysfunction and developmental disability. Current treatment is symptomatic and no existing medications target the specific cause of FXS. As with other X-linked disorders, FXS manifests differently in males and females, including abnormalities in the dopamine system that are also seen in Fmr1-knockout (KO) mice. We investigated sex differences in dopamine signaling in Fmr1-KO mice in response to L-stepholidine, a dopamine D1 receptor agonist and D2 receptor antagonist. We found significant sex differences in basal levels of phosphorylated protein kinase A (p-PKA) and glycogen synthase kinase (GSK)-3β in wild type mice that were absent in Fmr1-KO mice. In wild-type mice, L-stepholidine increased p-PKA in males but not female mice, decreased p-GSK-3 in female mice and increased p-GSK-3 in male mice. Conversely, in Fmr1-KO mice, L-stepholidine increased p-PKA and p-GSK-3β in females, and decreased p-PKA and p-GSK-3β in males.

scholarly journals Increased Pituitary Vascular Endothelial Growth Factor-A in Dopaminergic D2 Receptor Knockout Female Mice

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 2952-2962 ◽  
Author(s):  
C. Cristina ◽  
G. Díaz-Torga ◽  
A. Baldi ◽  
A. Góngora ◽  
M. Rubinstein ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
D2 Receptor ◽  
Prolactin Secretion ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Vegf Expression ◽  
Female Mice ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF)-A is an important angiogenic cytokine in cancer and pathological angiogenesis and has been related to the antiangiogenic activity of dopamine in endothelial cells. We investigated VEGF expression, localization, and function in pituitary hyperplasia of dopamine D2 receptor (D2R)-knockout female mice. Pituitaries from knockout mice showed increased protein and mRNA VEGF-A expression when compared with wild-type mice. In wild-type mice, prolonged treatment with the D2R antagonist, haloperidol, enhanced pituitary VEGF expression and prolactin release, suggesting that dopamine inhibits pituitary VEGF expression. VEGF expression was also increased in pituitary cells from knockout mice, even though these cells proliferated less in vitro when compared with wild-type cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium proliferation assay, proliferating cell nuclear antigen expression, and [3H]thymidine incorporation. In contrast to other animal models, estrogen did not increase pituitary VEGF protein and mRNA expression and lowered serum prolactin secretion in vivo and in vitro in both genotypes. VEGF (10 and 30 ng/ml) did not modify pituitary cell proliferation in either genotype and increased prolactin secretion in vitro in estrogen-pretreated cells of both genotypes. But conditioned media from D2R−/− cells enhanced human umbilical vein cell proliferation, and this effect could be partially inhibited by an anti-VEGF antiserum. Finally, using dual-labeling immunofluorescence and confocal laser microscopy, we found that in the hyperplastic pituitaries, VEGF-A was mostly present in follicle-stellate cells. In conclusion, pituitary VEGF expression is under dopaminergic control, and even though VEGF does not promote pituitary cellular proliferation in vitro, it may be critical for pituitary angiogenesis through paracrine actions in the D2R knockout female mice.

scholarly journals Behavior and Fos activation reveal that male and female rats differentially assess affective valence during CTA learning and expression

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260577
Author(s):  
Alyssa Bernanke ◽  
Elizabeth Burnette ◽  
Justine Murphy ◽  
Nathaniel Hernandez ◽  
Sara Zimmerman ◽  
...  
Keyword(s):  
Sex Differences ◽  
D2 Receptor ◽  
Brain Regions ◽  
D1 Receptor ◽  
Neural Mechanisms ◽  
Female Rats ◽  
Post Traumatic Stress ◽  
Affective Valence ◽  
Male And Female Rats ◽  
Males And Females

Females are more affected by psychiatric illnesses including eating disorders, depression, and post-traumatic stress disorder than males. However, the neural mechanisms mediating these sex differences are poorly understood. Animal models can be useful in exploring such neural mechanisms. Conditioned taste aversion (CTA) is a behavioral task that assesses how animals process the competition between associated reinforcing and aversive stimuli in subsequent task performance, a process critical to healthy behavior in many domains. The purpose of the present study was to identify sex differences in this behavior and associated neural responses. We hypothesized that females would value the rewarding stimulus (Boost®) relative to the aversive stimulus (LiCl) more than males in performing CTA. We evaluated behavior (Boost® intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), CTA performance) and Fos activation in relevant brain regions after the acute stimuli [acute Boost® (AB), acute LiCl (AL)] and the context-only task control (COT), Boost® only task (BOT) and Boost®-LiCl task (BLT). Acutely, females drank more Boost® than males but showed similar aversive behaviors after LiCl. Females and males performed CTA similarly. Both sexes produced 55 kHz USVs anticipating BOT and inhibited these calls in the BLT. However, more females emitted both 22 kHz and 55 kHz USVs in the BLT than males: the latter correlated with less CTA. Estrous cycle stage also influenced 55 kHz USVs. Fos responses were similar in males and females after AB or AL. Females engaged the gustatory cortex and ventral tegmental area (VTA) more than males during the BOT and males engaged the amygdala more than females in both the BOT and BLT. Network analysis of correlated Fos responses across brain regions identified two unique networks characterizing the BOT and BLT, in both of which the VTA played a central role. In situ hybridization with RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost® and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.

scholarly journals Inhibition of GSK-3β restores delayed gastric emptying in obesity-induced diabetic female mice

2020 ◽  
Vol 319 (4) ◽  
pp. G481-G493 ◽  
Author(s):  
Chethan Sampath ◽  
Shanthi Srinivasan ◽  
Michael L. Freeman ◽  
Pandu R. Gangula
Keyword(s):  
Gastric Emptying ◽  
Delayed Gastric Emptying ◽  
Glycogen Synthase ◽  
Related Factor ◽  
Female Mice ◽  
Downstream Signaling ◽  
Gsk 3Β ◽  
Sb 216763 ◽  
Oxide Synthase

Inhibition of glycogen synthase kinase 3β (GSK-3β) with SB 216763 attenuates delayed gastric emptying through gastric nuclear factor erythroid 2-related factor 2 (Nrf2) -phase II enzymes in high-fat diet-fed female mice. SB 216763 restored impaired gastric PI3K/AKT/ β-catenin/caspase 3 expression. Inhibition of GSK-3β normalized gastric dihydrofolate reductase, neuronal nitric oxide synthase-α expression, dimerization and nitrergic relaxation. SB 216763 normalized both serum estrogen and nitrate levels in female obese/Type 2 diabetes mice. SB 216763 reduced downstream signaling of GSK-3β in enteric neuronal cells in vitro.

scholarly journals Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Christian M Gallardo ◽  
Martin Darvas ◽  
Mia Oviatt ◽  
Chris H Chang ◽  
Mateusz Michalik ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
D1 Receptor ◽  
Circadian Oscillators ◽  
Food Anticipatory Activity ◽  
Dopamine Signaling ◽  
Anticipatory Activity ◽  
Dopamine Receptor 1 ◽  
Deficient Mice

Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output.

scholarly journals ERβ Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4352-4364 ◽  
Author(s):  
Ali Pedram ◽  
Mahnaz Razandi ◽  
Kenneth S. Korach ◽  
Ramesh Narayanan ◽  
James T. Dalton ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Glycogen Synthase ◽  
Wild Type ◽  
Cardiac Pathology ◽  
Cardiovascular Pathology ◽  
Female Mice ◽  
Selective Agonist ◽  
Transcription Factor Activation ◽  
Diastolic Hypertension

Cardiac hypertrophy in humans can progress to cardiac failure if the underlying impetus is poorly controlled. An important direct stimulator of hypertrophy and its progression is the angiotensin II (AngII) peptide. AngII also causes hypertension that indirectly contributes to cardiac hypertrophy. Others and we have shown that estrogens acting through the estrogen receptor (ER)-β can inhibit AngII-induced or other forms of cardiac hypertrophy in mice. However, the proliferative effects of estrogen in breast and uterus that promote the development of malignancy preclude using the steroid to prevent cardiac disease progression. We therefore tested whether an ERβ selective agonist, β-LGND2, can prevent hypertension and cardiac pathology in female mice. AngII infusion over 3 weeks significantly stimulated systolic and diastolic hypertension, cardiac hypertrophy, and cardiac fibrosis, all significantly prevented by β-LGND2 in wild-type but not in ERβ genetically deleted mice. AngII stimulated the Akt kinase to phosphorylate and inhibit the glycogen synthase kinase-3β kinase, leading to GATA4 transcription factor activation and hypertrophic mRNA expression. As a novel mechanism, all these actions were opposed by estradiol and β-LGND2. Our findings provide additional understanding of the antihypertrophic effects of ERβ and serve as an impetus to test specific receptor agonists in humans to prevent the worsening of cardiovascular disease.

scholarly journals Phosphorylation of tau by glycogen synthase kinase 3β affects the ability of tau to promote microtubule self-assembly

1997 ◽  
Vol 323 (3) ◽  
pp. 741-747 ◽  
Author(s):  
Michelle A. UTTON ◽  
André VANDECANDELAERE ◽  
Uta WAGNER ◽  
C. Hugh REYNOLDS ◽  
Graham M. GIBB ◽  
...  
Keyword(s):  
Self Assembly ◽  
Glycogen Synthase ◽  
Microtubule Assembly ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Wild Type ◽  
The Mean ◽  
Tau Isoform ◽  
Gsk 3Β ◽  
Mutant Forms

To study the effects of phosphorylation by glycogen synthase kinase-3β (GSK-3β) on the ability of the microtubule-associated protein tau to promote microtubule self-assembly, tau isoform 1 (foetal tau) and three mutant forms of this tau isoform were investigated. The three mutant forms of tau had the following serine residues, known to be phosphorylated by GSK-3, replaced with alanine residues so as to preclude their phosphorylation: (1) Ser-199 and Ser-202 (Ser-199/202 → Ala), (2) Ser-235 (Ser-235 → Ala) and (3) Ser-396 and Ser-404 (Ser-396/404 → Ala). Wild-type tau and the mutant forms of tau were phosphorylated with GSK-3β, and their ability to promote microtubule self-assembly was compared with the corresponding non-phosphorylated tau species. In the non-phosphorylated form, wild-type tau and all of the mutants affected the mean microtubule length and number concentrations of assembled microtubules in a manner consistant with enhanced microtubule nucleation. Phosphorylation of these tau species with GSK-3β consistently reduced the ability of a given tau species to promote microtubule self-assembly, although the affinity of the tau for the microtubules was not greatly affected by phosphorylation since the tau species remained largely associated with the microtubules. This suggests that the regulation of microtubule assembly can be controlled by phosphorylation of tau at sites accessible to GSK-3β by a mechanism that does not necessarily involve the dissociation of tau from the microtubules.

scholarly journals Degradation of Mcl-1 by β-TrCP Mediates Glycogen Synthase Kinase 3-Induced Tumor Suppression and Chemosensitization

2006 ◽  
Vol 27 (11) ◽  
pp. 4006-4017 ◽  
Author(s):  
Qingqing Ding ◽  
Xianghuo He ◽  
Jung-Mao Hsu ◽  
Weiya Xia ◽  
Chun-Te Chen ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Tumor Suppression ◽  
Glycogen Synthase ◽  
Tissue Homeostasis ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphorylation Sites ◽  
Wild Type ◽  
Gsk 3Β ◽  
Induced Apoptosis

ABSTRACT Apoptosis is critical for embryonic development, tissue homeostasis, and tumorigenesis and is determined largely by the Bcl-2 family of antiapoptotic and prosurvival regulators. Here, we report that glycogen synthase kinase 3 (GSK-3) was required for Mcl-1 degradation, and we identified a novel mechanism for proteasome-mediated Mcl-1 turnover in which GSK-3β associates with and phosphorylates Mcl-1 at one consensus motif (155 STDG159 SLPS163 T; phosphorylation sites are in italics), which will lead to the association of Mcl-1 with the E3 ligase β-TrCP, and β-TrCP then facilitates the ubiquitination and degradation of phosphorylated Mcl-1. A variant of Mcl-1 (Mcl-1-3A), which abolishes the phosphorylations by GSK-3β and then cannot be ubiquitinated by β-TrCP, is much more stable than wild-type Mcl-1 and able to block the proapoptotic function of GSK-3β and enhance chemoresistance. Our results indicate that the turnover of Mcl-1 by β-TrCP is an essential mechanism for GSK-3β-induced apoptosis and contributes to GSK-3β-mediated tumor suppression and chemosensitization.

scholarly journals Stimulation of glycogen synthesis by heat shock in L6 skeletal-muscle cells: regulatory role of site-specific phosphorylation of glycogen-associated protein phosphatase 1

2003 ◽  
Vol 371 (3) ◽  
pp. 857-866 ◽  
Author(s):  
Byoung MOON ◽  
Noreen DUDDY ◽  
Louis RAGOLIA ◽  
Najma BEGUM
Keyword(s):  
Heat Shock ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Shock Treatment ◽  
Protein Phosphatase 1 ◽  
Heat Shock Treatment ◽  
Wild Type ◽  
Gsk 3Β ◽  
Phosphoinositide 3 Kinase

Recent evidence suggests that glycogen-associated protein phosphatase 1 (PP-1G) is essential for basal and exercise-induced glycogen synthesis, which is mediated in part by dephosphorylation and activation of glycogen synthase (GS). In the present study, we examined the potential role of site-specific phosphorylation of PP-1G in heat-shock-induced glycogen synthesis. L6 rat skeletal-muscle cells were stably transfected with wild-type PP-1G or with PP-1G mutants in which site-1 (S1) Ser48 and site-2 (S2) Ser67 residues were substituted with Ala. Cells expressing wild-type and PP-1G mutants, S1, S2 and S1/S2, were examined for potential alterations in glycogen synthesis after a 60min heat shock at 45°C, followed by analysis of [14C]glucose incorporation into glycogen at 37°C. PP-1G S1 mutation caused a 90% increase in glycogen synthesis on heat-shock treatment, whereas the PP-1G S2 mutant was not sensitive to heat stress. The S1/S2 double mutant was comparable with wild-type, which showed a 30% increase over basal. Heat-shock-induced glycogen synthesis was accompanied by increased PP-1 and GS activities. The highest activation was observed in S1 mutant. Heat shock also resulted in a rapid and sustained Akt/ glycogen synthase kinase 3β (GSK-3β) phosphorylation. Wortmannin blocked heat-shock-induced Akt/GSK-3β phosphorylation, prevented 2-deoxyglucose uptake and abolished the heat-shock-induced glycogen synthesis. Muscle glycogen levels regulate GS activity and glycogen synthesis and were found to be markedly depleted in S1 mutant on heat-shock treatment, suggesting that PP-1G S1 Ser phosphorylation may inhibit glycogen degradation during thermal stimulation, as S1 mutation resulted in excessive glycogen synthesis on heat-shock treatment. In contrast, PP-1G S2 Ser phosphorylation may promote glycogen breakdown under stressful conditions. Heat-shock-induced glycogenesis appears to be mediated via phosphoinositide 3-kinase/Akt-dependent GSK-3β inactivation as well as phosphoinositide 3-kinase-independent PP-1 activation.

scholarly journals β-TrCP-Mediated Ubiquitination and Degradation of PHLPP1 Are Negatively Regulated by Akt

2009 ◽  
Vol 29 (23) ◽  
pp. 6192-6205 ◽  
Author(s):  
Xin Li ◽  
Jianyu Liu ◽  
Tianyan Gao
Keyword(s):  
High Frequency ◽  
Opposite Effect ◽  
Glycogen Synthase ◽  
Degradation Process ◽  
Dependent Manner ◽  
Wild Type ◽  
Phosphatidylinositol 3 Kinase ◽  
Casein Kinase I ◽  
Gsk 3Β ◽  
F Box Protein

ABSTRACT PHLPP1 belongs to a novel family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating Akt signaling. Our recent studies have demonstrated that loss of PHLPP expression occurs at high frequency in colorectal cancer. In this study, we identified PHLPP1 as a proteolytic target of a β-TrCP-containing Skp-Cullin 1-F-box protein (SCF) complex (SCFβ-TrCP) E3 ubiquitin ligase in a phosphorylation-dependent manner. Overexpression of wild-type but not ΔF-box mutant β-TrCP leads to decreased expression and increased ubiquitination of PHLPP1, whereas knockdown of endogenous β-TrCP has the opposite effect. In addition, we show that the β-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3β (GSK-3β), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3β activity. Furthermore, expression of a degradation-deficient PHLPP1 mutant in colon cancer cells results in a more effective dephosphorylation of Akt and inhibition of cell growth. Taken together, our findings demonstrate a key role for β-TrCP in controlling the level of PHLPP1, and activation of Akt negatively regulates this degradation process.

Synthesis of Coumarin Derivatives as Versatile Scaffolds for GSK-3β Enzyme Inhibition

2020 ◽  
Vol 20 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Carla S. Francisco ◽  
Clara L. Javarini ◽  
Iatahanderson de S. Barcelos ◽  
Pedro A.B. Morais ◽  
Heberth de Paula ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Glycogen Synthase ◽  
Synthetic Methods ◽  
Kinase Assay ◽  
Crystallographic Structure ◽  
Coumarin Derivatives ◽  
Enzymatic Production ◽  
Docking Simulations ◽  
In Silico Studies ◽  
Gsk 3Β

Background: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3β isoforms is likely to represent an effective strategy against AD. Objective: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3β kinase inhibitors. Method: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3β activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3β complex [Protein Data Bank (PDB) code: 1Q3D]. Results: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3β enzymatic activity by 38.97–49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224–6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. Conclusion: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3β inhibitors.

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