Functional and pharmacological explorations of quercetin-like compounds on glucose-induced insulin secretion

International audienc

Functional and pharmacological explorations of quercetin-like compounds on glucose-induced insulin secretion

International audienc

Functional and pharmacological explorations of quercetin-like compounds on glucose-induced insulin secretion

International audienc

Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse

Relapse to alcohol abuse is an important clinical issue that is frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue-alcohol association is expected to prevent relapse. It is increasingly accepted that memories be

Effets et mécanismes d’action d'analogues structuraux de la quercétine sur la sécrétion d'insuline induite par le glucose

International audienc

Inhibition of transcription by B cell leukaemia 3 (Bcl-3) requires interaction with nuclear factor (NF)-κB p50

B cell leukaemia (Bcl)-3 is an essential negative regulator of Nuclear Factor (NF)-κB during Toll-Like Receptor (TLR) and TNF Receptor signalling. Bcl-3 also interacts with a number of transcriptional regulators including homodimers of the NF-κB p50 subunit. Deletion of Bcl-3 results in increased NF-κB p50 ubiquitination and proteasomal degradation, and increased inflammatory gene expression. We have employed immobilised peptide array technology to define a region of p50 required for the formation of a Bcl-3:p50 homodimer immunosuppressor complex. Our data demonstrates that amino acids 359-361 and 363 of p50 are critical for interaction with Bcl-3 and are essential for Bcl-3 mediated inhibition of inflammatory gene expression. Bcl-3 is unable to interact with p50 when these amino acids are mutated, rendering it incapable of inhibiting the transcriptional activity of NF-κB. Bcl-3-interaction defective p50 is hyper-ubiquitinated and has a significantly reduced half-life relative to wild type p50. Nfkb1-/- cells reconstituted with mutated p50 precursor p105 are hyper-responsive to TNFα stimulation relative to wild type p105 as measured by inflammatory gene expression. Mutant p105 recapitulates a Bcl3-/- phenotype. This study demonstrates that interaction with p50 is necessary and sufficient for the anti-inflammatory properties of Bcl-3 and further highlights the importance of p50 homodimer stability in the control of NF-κB target gene expression

MTORC1-dependent translation of collapsin response mediator protein-2 drives neuroadaptations underlying excessive alcohol-drinking behaviors

Mammalian target of rapamycin complex 1 (mTORC1) has an essential role in dendritic mRNA translation and participates in mechanisms underlying alcohol-drinking and reconsolidation of alcohol-related memories. Here, we report that excessive alcohol consumption increases the translation of downstream targets of mTORC1, including collapsin response mediator protein-2 (CRMP-2), in the nucleus accumbens (NAc) of rodents. We show that alcohol-mediated induction of CRMP-2 translation is mTORC1-dependent, leading to increased CRMP-2 protein levels. Furthermore, we demonstrate that alcohol intake also blocks glycogen synthase kinase-3β (GSK-3β)-phosphorylation of CRMP-2, which results in elevated binding of CRMP-2 to microtubules and a concomitant increase in microtubule content. Finally, we show that systemic administration of the CRMP-2 inhibitor lacosamide, or knockdown of CRMP-2 in the NAc decreases excessive alcohol intake. These results suggest that CRMP-2 in the NAc is a convergent point that receives inputs from two signaling pathways, mTORC1 and GSK-3β, that in turn drives excessive alcohol-drinking behaviors. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved

Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse

Relapse to alcohol abuse is a critical clinical issue, frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue-alcohol association is expected to prevent relapse. It is increasingly accepted that memories become labile and erasable soon after their reactivation through retrieval, during a memory reconsolidation process that depends on protein synthesis. Here, we show that reconsolidation of alcohol-related memories triggered by the sensory properties of alcohol itself (odor and taste) activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions in rats, resulting in increased levels of several synaptic proteins. Furthermore, systemic or central amygdalar (CeA) inhibition of mTORC1 during reconsolidation disrupts alcohol-cue associated memories, leading to a long-lasting suppression of relapse. Our findings provide evidence that the mTORC1 pathway and its downstream substrates play a crucial role in alcohol-related memory reconsolidation, and highlight this pathway as a therapeutic target to prevent relapse