2017
DOI: 10.3389/fncel.2017.00152
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mTORC1 Is a Local, Postsynaptic Voltage Sensor Regulated by Positive and Negative Feedback Pathways

Abstract: The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) serves as a regulator of mRNA translation. Recent studies suggest that mTORC1 may also serve as a local, voltage sensor in the postsynaptic region of neurons. Considering biochemical, bioinformatics and imaging data, we hypothesize that the activity state of mTORC1 dynamically regulates local membrane potential by promoting and repressing protein synthesis of select mRNAs. Our hypothesis suggests that mTORC1 uses positive and negative feedback pa… Show more

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Cited by 26 publications
(21 citation statements)
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References 147 publications
(227 reference statements)
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“…mTORC1 activation can increase protein synthesis of some, yet repress translation of other specific proteins. Thereby deviations to an optimal range of protein synthesis that adapts to demand results in the behavioral impairments that develop with age (34)(35)(36)(37). Notably, our data showing that rapamycin treatment increases UCH-L1 protein in Uch-l1 +/+ and Uch-l1 +/d neurons demonstrates that mTORC1 inhibition can also induce protein synthesis of particular homeostatic proteins, such as UCH-L1, important in the regulation of protein synthesis.…”
Section: Discussionmentioning
confidence: 72%
“…mTORC1 activation can increase protein synthesis of some, yet repress translation of other specific proteins. Thereby deviations to an optimal range of protein synthesis that adapts to demand results in the behavioral impairments that develop with age (34)(35)(36)(37). Notably, our data showing that rapamycin treatment increases UCH-L1 protein in Uch-l1 +/+ and Uch-l1 +/d neurons demonstrates that mTORC1 inhibition can also induce protein synthesis of particular homeostatic proteins, such as UCH-L1, important in the regulation of protein synthesis.…”
Section: Discussionmentioning
confidence: 72%
“…Slc7a5 is thought to influence mTOR activity, due to activation of the mTOR complex by amino acids like leucine (Nicklin et al, 2009;Saxton et al, 2016;Wolfson et al, 2016) . Also, mTOR signaling has been shown to modulate Kv1.1 translation in dendrites, although this mechanism is unlikely to be involved here, as it was shown to rely on UTR elements that are not present in our Kv1.1 cDNA (Niere and Raab-Graham, 2017;Raab-Graham et al, 2006) . We used a variety of pharmacological tools including direct inhibition of Slc7a5 transport (BCH), and mTOR inhibition (rapamycin), but found no effect on Kv1.1 regulation by Slc7a5.…”
Section: Discussionmentioning
confidence: 94%
“…The Kv1 family are important components controlling the somatodendritic excitability in sensory neurons (48) and MSNs (49). Importantly, mTOR has been shown to dampen excitability by increasing Kv1.1 channel function in hippocampal neurons (7, 40). Hence, we hypothesized that some of the behavioural alterations observed in D 1 -mTOR KO mice are caused by changes in electrophysiological properties.…”
Section: Resultsmentioning
confidence: 99%
“…Upon activation, mTORC1 promotes protein synthesis by phosphorylating translation regulators, including p70S6K and 4EBP1 (5, 6). In addition to its control in mRNA translation, mTORC1 has been described as a postsynaptic voltage sensor, controlling the excitability of neurons (7). In addition, RhoA, which recently has been mechanistically connected to autistic-like behaviour (with marked modifications on locomotion and social skills) in mice after the deletion of the TAOK2 gene (8) and an important mediator of protein recycling in mammalian cells, is connected to the activity of the mTORC1 pathway (9).…”
Section: Introductionmentioning
confidence: 99%