The Cationic Amino Acid Transporters CAT1 and CAT3 Mediate NMDA Receptor Activation-Dependent Changes in Elaboration of Neuronal Processes via the Mammalian Target of Rapamycin mTOR Pathway

Huang, Yunfei; Kang, Bingnan N.; Tian, Jing; Liu‐Chittenden, Yi; Luo, Hongbo; Hester, Lynda D.; Snyder, Solomon H.

doi:10.1523/jneurosci.4489-06.2007

Cited by 54 publications

(50 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NMDA receptor activation is an important regulator of mTOR signaling activity (Huang et al, 2007) (Fig. 1).…”

Section: Nmda Regulation Of Mtor Activitymentioning

confidence: 99%

“…1). Specifically, sustained NMDA receptor activation leads to the rapid internalization of two isoforms of the cationic amino acid transporter, resulting in diminished arginine transport into cortical neurons (Huang et al, 2007). Intraneuronal concentrations of arginine are detected by ‘nutrient sensors’ that influence mTORCl activity.…”

Section: Nmda Regulation Of Mtor Activitymentioning

confidence: 99%

“…Intraneuronal concentrations of arginine are detected by ‘nutrient sensors’ that influence mTORCl activity. Thus, when intraneuronal concentrations of arginine are low, mTORCl activity is dampened, resulting in diminished rates and amounts of protein synthesis (Huang et al, 2007). Further, NMDA receptor activation regulates the duration of signaling by the phosphorylated form of extracellular signal regulated kinase 1/2 (ERK1/2), an important driver of mTORCl activity.…”

Section: Nmda Regulation Of Mtor Activitymentioning

confidence: 99%

See 2 more Smart Citations

NMDA receptor activation regulates sociability by its effect on mTOR signaling activity

Burket

Benson

Tang

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

View full text Add to dashboard Cite

Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORCl in neurons (e.g., cerebellar Purkinje cells). mTORCl is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORCl, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORCl overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORCl activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are “drivers” of mTORCl activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.

show abstract

“…NMDA receptor activation is an important regulator of mTOR signaling activity (Huang et al, 2007) (Fig. 1).…”

Section: Nmda Regulation Of Mtor Activitymentioning

confidence: 99%

Section: Nmda Regulation Of Mtor Activitymentioning

confidence: 99%

Section: Nmda Regulation Of Mtor Activitymentioning

confidence: 99%

See 1 more Smart Citation

NMDA receptor activation regulates sociability by its effect on mTOR signaling activity

Burket

Benson

Tang

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

View full text Add to dashboard Cite

show abstract

“…In addition to electrophysiological consequences of glutamate-gated calcium ion entry, there are a host of metabolic consequences related to the transient increase in calcium ion concentrations. Very interestingly, NMDA receptor activation affects signalling activity by the mammalian target of rapamycin (mTOR), a serine/threonine kinase, contained within the mTORC1 complex, which influences transcription and translation [10–12]. For example, NMDA receptor activation results in the negative regulation of cationic amino acid transporters within the cell’s plasma membrane, which are responsible for arginine transport into the cell, causing their rapid internalization and lowering of intracellular levels of arginine.…”

Section: Introductionmentioning

confidence: 99%

“…For example, NMDA receptor activation results in the negative regulation of cationic amino acid transporters within the cell’s plasma membrane, which are responsible for arginine transport into the cell, causing their rapid internalization and lowering of intracellular levels of arginine. Lowered intracellular arginine concentrations are detected by “nutrient sensors” that lead to dampening of mTOR signalling activity [10]. Furthermore, NMDA receptor activation leads to the Ca 2+ -dependent activation of calcineurin, a protein phosphatase, whose substrates include STriatal Enriched protein tyrosine Phosphatase (STEP).…”

Section: Introductionmentioning

confidence: 99%

NMDA receptors on the surface of cancer cells: Target for chemotherapy?

Deutsch

Tang

Burket

et al. 2014

Biomedicine & Pharmacotherapy

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a therapeutic target for many types of cancers. NMDA receptors regulate mTOR signalling activity; their inappropriate expression on several human cancer cell lines represents a potential therapeutic avenue to control dysregulated growth, division and invasiveness. Targeting these receptors with selective ligands (e.g., glycineB site ligands) may be a less toxic and more tolerable approach than administering compounds acting at the mTORC1 complex itself, such as rapamycin and its derivatives. Thus, testing glycineB site ligands in relevant in vitro and in vivo paradigms with established human cancer cells that express NMDA receptors on their surface could provide proofs of concept/principle that would encourage exploration of these and other “non-toxic” strategies. Interestingly, in some cancer models that express NMDA receptors on their surface, NMDA receptor antagonists, such as MK-801 (dizocilpine), were shown to possess anti-proliferative and anti-invasive effects, which conflict with hypotheses about promoting NMDA receptor activation as a cancer chemotherapeutic strategy. Whether NMDA receptor activation or antagonism is associated with anti-proliferative and anti-invasive effects may reflect differences between cancer cell lines in terms of the proteins associated with the NMDA receptors on their cell surfaces, which, in turn, could lead to different “downstream” effects on cascades of intracellular phosphorylations. Irrespective of whether activation or antagonism is associated with anti-proliferative and anti-invasive effects for specific types of cancer, data are emerging that support exploration of targeting NMDA receptors expressed on the surface of cancer cells as a therapeutic strategy.

show abstract

Duloxetine ameliorates valproicacid‐inducedhyperactivity, anxiety‐like behavior, and social interaction deficits in zebrafish

et al. 2021

View full text Add to dashboard Cite

Syndromic autism spectrum disorders (ASDs) are characterized by impaired social communication and repetitive/stereotyped behaviors. Currently available therapeutic agents against ASD have limited efficacy. Thus, searching for novel and effective drugs ameliorating core symptoms, in particular social deficits, is of utmost importance. Duloxetine (DLX), an antidepressant that has been identified as an agonist mimetic for the cell adhesion molecule L1, exhibits beneficial functions in vitro and in vivo. Therefore, in this study, we focused on the rapid and persistent neuroprotective function of DLX following valproic acid (VPA)‐triggered hyperactivity, anxiety‐like behavior and social deficits in zebrafish. Embryonic exposure to VPA reduced survival in a dose‐ and time‐dependent manner, delayed hatching, and also resulted in a significant number of malformed larvae. After initial dose–response experiments in zebrafish larvae, 10 μM VPA exposure between 0.33 and 4.5 days post fertilization (dpf) was identified as an effective concentration that led to an early and persistent ASD‐like phenotype in zebrafish. ASD‐like elevated acetylcholine esterase (AChE) activity and reduced Akt–mTOR signaling was observed in zebrafish whole brain. Acute administration of DLX (4.5–6 dpf) reduced the VPA‐induced ASD‐like phenotype in zebrafish larvae. Additionally, such early‐life acute DLX treatment had long‐term effects in ameliorating social impairments, hyperactivity, and anxiety‐like behaviors through adulthood. This was accompanied by reduced AChE activity and by normalized Akt–mTOR signaling. Overall, DLX treatment showed a long‐term therapeutic effect on autistic‐like behaviors, and alteration of AChE activity and Akt–mTOR signaling were identified as crucial in the VPA‐induced ASD zebrafish model.

show abstract

The Cationic Amino Acid Transporters CAT1 and CAT3 Mediate NMDA Receptor Activation-Dependent Changes in Elaboration of Neuronal Processes via the Mammalian Target of Rapamycin mTOR Pathway

Cited by 54 publications

References 56 publications

NMDA receptor activation regulates sociability by its effect on mTOR signaling activity

NMDA receptor activation regulates sociability by its effect on mTOR signaling activity

NMDA receptors on the surface of cancer cells: Target for chemotherapy?

Duloxetine ameliorates valproicacid‐inducedhyperactivity, anxiety‐like behavior, and social interaction deficits in zebrafish

Contact Info

Product

Resources

About