scholarly journals mTORC1 In the Orbitofrontal Cortex Promotes Habitual Alcohol Seeking

2019 ◽  
Author(s):  
Nadege Morisot ◽  
Anthony L. Berger ◽  
Khanhky Phamluong ◽  
Sophie Laguesse ◽  
Jeffrey J. Moffat ◽  
...  
Keyword(s):  
Orbitofrontal Cortex ◽  
Alcohol Withdrawal ◽  
Mammalian Target Of Rapamycin ◽  
Adaptor Protein ◽  
Random Ratio ◽  
Alcohol Habit ◽  
Heavy Alcohol Use ◽  
Habitual Responding ◽  
Mtorc1 Activation ◽  
Alcohol Seeking

AbstractThe mammalian target of rapamycin complex 1 (mTORCl) plays an important role in dendritic translation, synaptic plasticity, and learning and memory. We previously showed that heavy alcohol use activates mTORC1 in the orbitofrontal cortex (OFC) of rodents. Here, we set out to determine the consequences of alcohol-dependent mTORC1 activation in the OFC. We found that although inhibition of mTORC1 in the OFC does not alter rat alcohol intake per se, it attenuates alcohol seeking. We then tested whether mTORC1 in the OFC is required for goal-directed or habitual alcohol seeking. To do so, rats were trained self-administer alcohol under a random ratio (RR) or a random interval (RI) schedule of reinforcement, which biases toward goal-directed or habitual responding, respectively, and tested whether mTORC1 inhibition alters lever presses following alcohol devaluation. We found that pharmacological inhibition of mTORC1 or knockdown of the adaptor protein, Raptor, did not affect goal-directed alcohol responding but restored sensitivity to devaluation in RI-trained rats. In contrast, habitual responding for sucrose was unaltered by mTORC1 inhibition. These data suggest that mTORC1 in the OFC drives alcohol habit. We then elucidate the mechanism by which mTORC1 is activated by alcohol, and found that the recruitment of GluN2B during alcohol withdrawal stimulates mTORC1 in OFC cFos-positive neurons. Finally, we show that inhibition of GluN2B in the OFC attenuates both alcohol seeking and habitual responding for alcohol. Together, our data suggest that alcohol withdrawal promotes an NMDAR-dependent activation of mTORC1 which in turn drives habitual alcohol seeking.

scholarly journals mTORC1 in the orbitofrontal cortex promotes habitual alcohol seeking

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Nadege Morisot ◽  
Khanhky Phamluong ◽  
Yann Ehinger ◽  
Anthony L Berger ◽  
Jeffrey J Moffat ◽  
...  
Keyword(s):  
Orbitofrontal Cortex ◽  
Heavy Alcohol ◽  
Mechanistic Target Of Rapamycin ◽  
Heavy Alcohol Use ◽  
Habitual Behavior ◽  
Habitual Responding ◽  
Mtorc1 Activation ◽  
Outcome Devaluation ◽  
Alcohol Seeking ◽  
Alcohol Dependent

The mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in dendritic translation and in learning and memory. We previously showed that heavy alcohol use activates mTORC1 in the orbitofrontal cortex (OFC) of rodents (Laguesse et al., 2017a). Here, we set out to determine the consequences of alcohol-dependent mTORC1 activation in the OFC. We found that inhibition of mTORC1 activity in the OFC attenuates alcohol seeking and restores sensitivity to outcome devaluation in rats that habitually seek alcohol. In contrast, habitual responding for sucrose was unaltered by mTORC1 inhibition, suggesting that mTORC1’s role in habitual behavior is specific to alcohol. We further show that inhibition of GluN2B in the OFC attenuates alcohol-dependent mTORC1 activation, alcohol seeking and habitual responding for alcohol. Together, these data suggest that the GluN2B/mTORC1 axis in the OFC drives alcohol seeking and habit.

scholarly journals Leucyl-tRNA Synthetase Deficiency Systemically Induces Excessive Autophagy in Zebrafish

2021 ◽  
Author(s):  
Hiroshi Shiraishi ◽  
Nobuyuki Shimizu ◽  
Mika Tsumori ◽  
Kyoko Kiyota ◽  
Miwako Maeda ◽  
...  
Keyword(s):  
Liver Failure ◽  
Mammalian Target Of Rapamycin ◽  
Trna Synthetase ◽  
Biallelic Mutation ◽  
Synthetase Deficiency ◽  
Morpholino Knockdown ◽  
Mtorc1 Activation ◽  
Early Lethality

Abstract Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb-/-) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb-/- zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb-/- zebrafish. Indeed, excessive autophagy activation was observed in larsb-/- zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.

Daily protein supplementation attenuates immobilization-induced blunting of postabsorptive muscle mTORC1 activation in middle age men

2021 ◽  
Author(s):  
Nina Zeng ◽  
Randall F. D'Souza ◽  
Caitlin L. Macrae ◽  
Vandre C. Figueiredo ◽  
Chantal A. Pileggi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Primary Objective ◽  
Protein Supplementation ◽  
Anabolic Resistance ◽  
Pathway Activation ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation

Disuse-induced muscle atrophy is accompanied by a blunted postprandial response of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Conflicting observations exist as to whether postabsorptive mTORC1 pathway activation is also blunted by disuse and plays a role in atrophy. It is unknown whether changes in habitual protein intake alters mTORC1 regulatory proteins and how they may contribute to the development of anabolic resistance. The primary objective of this study was to characterize the downstream responsiveness of skeletal muscle mTORC1 activation and its upstream regulatory factors, following 14 days of lower limb disuse in middle-aged men (45-60 years). The participants were further randomized to receive daily supplementation of 20g/d of protein (n=12; milk protein concentrate) or isocaloric carbohydrate placebo (n=13). Immobilization reduced postabsorptive skeletal muscle phosphorylation of the mTORC1 downstream targets, 4E-BP1, P70S6K and ribosomal protein S6 (RPS6), with phosphorylation of the latter two decreasing to a greater extent in the placebo, compared to the protein supplementation groups (37 ± 13 vs 14 ± 11% and 38 ± 20 vs 25 ± 8% respectively). Sestrin2 protein was also downregulated following immobilization irrespective of supplement group, despite a corresponding increase in its mRNA content. This decrease in Sestrin2 protein was negatively correlated with the immobilization induced change in the in-silico predicted regulator miR-23b-3p. No other measured upstream proteins were altered by immobilization or supplementation. Immobilization downregulated postabsorptive mTORC1 pathway activation and 20g/day of protein supplementation attenuated the decrease in phosphorylation of targets regulating muscle protein synthesis.

scholarly journals NF2/Merlin Is a Novel Negative Regulator of mTOR Complex 1, and Activation of mTORC1 Is Associated with Meningioma and Schwannoma Growth

2009 ◽  
Vol 29 (15) ◽  
pp. 4250-4261 ◽  
Author(s):  
Marianne F. James ◽  
Sangyeul Han ◽  
Carolyn Polizzano ◽  
Scott R. Plotkin ◽  
Brendan D. Manning ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Suppressor Activity ◽  
Mtorc1 Signaling ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Tumor Suppressive Function ◽  
Mtorc1 Activation

ABSTRACT Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

2014 ◽  
Vol 307 (9) ◽  
pp. F1023-F1032 ◽  
Author(s):  
Junhua Mao ◽  
Zhifeng Zeng ◽  
Zhuo Xu ◽  
Jiangzhong Li ◽  
Lei Jiang ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Target Of Rapamycin ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Mtorc1 Signaling ◽  
Cellular Crescent ◽  
Underlying Mechanisms ◽  
Mtorc1 Activation ◽  
Glomerular Tuft

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

scholarly journals Single Serine on TSC2 Exerts Biased Control over mTORC1 Activation by ERK1/2 but Not Akt

2021 ◽  
Author(s):  
Brittany L. Dunkerly-Eyring ◽  
Miguel Pinilla-Vera ◽  
Desirae McKoy ◽  
Sumita Mishra ◽  
Maria Iziar Grajeda Martinez ◽  
...  
Keyword(s):  
Fatty Liver Disease ◽  
Regulatory Mechanism ◽  
Mammalian Target Of Rapamycin ◽  
Protein Kinase G ◽  
Environmental Cues ◽  
Insulin Stimulation ◽  
Co Activation ◽  
Kinase Phosphorylation ◽  
Mtorc1 Activation ◽  
Stimulation Of

The mammalian target of rapamycin complex 1 (mTORC1) is tightly controlled by tuberous sclerosis complex-2 (TSC2), itself regulated by kinase phosphorylation reflecting environmental cues. Among these kinases is protein kinase G that modifies TSC2 at S1365 (S1364, human). This minimally affects basal mTORC1 activity, but upon phosphorylation or with an SE mutation, it blocks mTORC1 co-activation by pathological stress. An SA (phospho-silenced) mutation does the opposite. Here we reveal S1365 exerts biased regulation over mTORC1 activity (S6K phosphorylation). In myocytes and fibroblasts, ERK1/2 stimulated mTORC1 via endothelin-1 (ET-1) is potently and bidirectionally regulated by S1365. By contrast, Akt stimulation of mTORC1 (insulin) is minimally impacted. S1365 phosphorylation rises with ET-1 but not insulin stimulation, supporting intrinsic engagement by one and not the other. Energy and nutrient modulation of mTORC1 are minimally influenced by S1365. Consistent with these findings, knock-in mice with SA or SE mutations develop identical obesity, glucose intolerance, and fatty liver disease. These results reveal an ERK1/2-biased TSC2 regulatory mechanism controlling mTORC1 activation, with implications for suppressing pathological but not physiological mTORC1 stimulation.

scholarly journals Insights into the Interaction of Lysosomal Amino Acid Transporters SLC38A9 and SLC36A1 Involved in mTORC1 Signaling in C2C12 Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1314
Author(s):  
Dan Wang ◽  
Xuebin Wan ◽  
Xiaoli Du ◽  
Zhuxia Zhong ◽  
Jian Peng ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Skeletal Muscle Mass ◽  
Mammalian Target Of Rapamycin ◽  
C2c12 Cells ◽  
Amino Acid Transporters ◽  
Interacting Proteins ◽  
Mtorc1 Signaling ◽  
Amino Acid Sensing ◽  
Mtorc1 Activation

Amino acids are critical for mammalian target of rapamycin complex 1 (mTORC1) activation on the lysosomal surface. Amino acid transporters SLC38A9 and SLC36A1 are the members of the lysosomal amino acid sensing machinery that activates mTORC1. The current study aims to clarify the interaction of SLC38A9 and SLC36A1. Here, we discovered that leucine increased expressions of SLC38A9 and SLC36A1, leading to mTORC1 activation. SLC38A9 interacted with SLC36A1 and they enhanced each other’s expression levels and locations on the lysosomal surface. Additionally, the interacting proteins of SLC38A9 in C2C12 cells were identified to participate in amino acid sensing mechanism, mTORC1 signaling pathway, and protein synthesis, which provided a resource for future investigations of skeletal muscle mass.

Mammalian target of rapamycin is activated in the kidneys of patients with scleroderma renal crisis

2019 ◽  
Vol 5 (2) ◽  
pp. 152-158
Author(s):  
Jessica Salituri ◽  
Natalie Patey ◽  
Tomoko Takano ◽  
Pierre Fiset ◽  
Sonia Del Rincon ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Vascular Lesions ◽  
Scleroderma Renal Crisis ◽  
Renal Vasculature ◽  
Renal Biopsies ◽  
Mtorc1 Activation ◽  
Arterial Endothelial Cells ◽  
Renal Crisis

Objectives: Scleroderma renal crisis is a rare but serious complication affecting 2%–15% of patients with systemic sclerosis. Despite treatment with angiotensin-converting enzyme inhibitors, outcomes for scleroderma renal crisis patients are still poor. The cellular signaling mechanisms in scleroderma renal crisis are not yet known. Mammalian target of rapamycin, comprised of the subunits mTORC1 and mTORC2, has been shown to be activated in vascular lesions of renal transplant patients with anti-phospholipid antibody syndrome. Given the similarities between the pathophysiology of scleroderma renal crisis and anti-phospholipid antibody syndrome, we hypothesized that the mammalian target of rapamycin pathway would also be activated in the renal vasculature of patients with scleroderma renal crisis. Methods: We retrospectively analyzed renal biopsies of five patients with scleroderma renal crisis in the Canadian Scleroderma Research Group cohort. Immunostaining was performed using anti-P-S6RP antibodies to evaluate the phosphorylation of mTORC1, and anti-Rictor and anti-S473 to determine activation of mTORC2. Results: Four of the five patients showed mTORC1 activation in arteriolar endothelial cells, and three of the five patients showed mTORC1 activation in the arterial endothelial cells. Two of four samples showed Rictor expression in the arteriolar and arterial endothelial cells, showing mTORC2 activation. There was no expression of mTORC1 or mTORC2 in samples from two healthy controls. Conclusion: We demonstrate that both mTORC1 and mTORC2 are activated in renal biopsies with typical histologic features of scleroderma renal crisis. Dual mammalian target of rapamycin inhibitors are currently available and in development. These findings could inform further research into novel treatment targets for scleroderma renal crisis.

scholarly journals LncRNA coordinates Hippo and mTORC1 pathway activation in cancer

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Shugeng Zhang ◽  
Shuhang Liang ◽  
Dehai Wu ◽  
Hongrui Guo ◽  
Kun Ma ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Tumour Growth ◽  
Hippo Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Growth Control ◽  
Nuclear Accumulation ◽  
Control Functions ◽  
Pathway Activation ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation

AbstractThe Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant pathways that regulate tumour growth and metastasis. Therefore, we explored the potential crosstalk between these two functionally relevant pathways to coordinate their tumour growth-control functions. We found that a Hippo pathway-related long noncoding RNA, HPR, directly interacts with Raptor, an essential component of mTORC1, to upregulate mTORC1 activation by impairing the phosphorylation of Raptor by AMPK. Knockdown or knockout of HPR in breast cancer and cholangiocarcinoma cells led to a reduction in tumour growth. Compared with HPR WT cells, HPR-overexpressing cells exhibited nuclear accumulation of YAP1, and significantly blocked the downregulation of mTORC1 signalling induced by energy stress. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways in the control of tumour growth.

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