Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Lin, Amy; Man, Heng‐Ye

doi:10.1155/2013/432057

Cited by 29 publications

(29 citation statements)

References 76 publications

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“…Several synaptic proteins are regulated by the ubiquitin-proteasome system (see (Lin and Man, 2013; Mabb and Ehlers, 2010) for recent reviews). For instance, PSD-95 is ubiquitinated by the E3 ligase Mdm2 leading to subsequent degradation by proteasomes in response to NMDA receptor activation (Colledge et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

et al. 2015

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Summary Gated solely by activity-induced changes in intracellular calcium, small conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics and Ca2+ sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and over-expression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function.

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Section: Discussionmentioning

confidence: 99%

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

et al. 2015

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“…Protein ubiquitination emerged as one of the enriched functions. Ubiquitination and proteasome-mediated degradation have been suggested as universal mechanisms in the control of synaptic protein homeostasis and have already been associated with ASD neurobiology [Glessner et al, 2009;Lin and Man, 2013;Crider et al, 2014]. The overall scenario suggests that the biology of ASD is linked to basal cell processes, also underlying synaptic function.…”

Section: Discussionmentioning

confidence: 99%

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Schuch

Paixão‐Côrtes

Friedrich

et al. 2016

American J of Med Genetics Pt B

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Several autism spectrum disorders (ASD) exome studies suggest that coding single nucleotide variants (SNVs) play an important role on ASD etiology. Usually, the pathogenic effect of missense mutations is estimated through predictors that lose accuracy for those SNVs placed in intrinsically disordered regions of protein. Here, we used bioinformatics tools to investigate the effect of mutations described in ASD published exome studies (549 mutations) in protein disorder, considering post-translational modification, PEST and Molecular Recognition Features (MoRFs) motifs. Schizophrenia and type 2 diabetes (T2D) datasets were created for comparison purposes. The frequency of mutations predicted as disordered was comparable among the three datasets (38.1% in ASD, 35.7% in schizophrenia, 46.4% in T2D). However, the frequency of SNVs predicted to lead a gain or loss of functional sites or change intrinsic disorder tendencies was higher in ASD and schizophrenia than T2D (46.9%, 36.4%, and 23.1%, respectively). The results obtained by SIFT and PolyPhen-2 indicated that 38.9% and 34.4% of the mutations predicted, respectively, as tolerated and benign showed functional alterations in disorder properties. Given the frequency of mutations placed in IDRs and their functional impact, this study suggests that alterations in intrinsic disorder properties might play a role in ASD and schizophrenia etiologies. They should be taken into consideration when researching the pathogenicity of mutations in neurodevelopmental and psychiatric diseases. Finally, mutations with functional alterations in disorder properties must be potential targets for in vitro and in vivo functional studies.

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“…Protein degradation via the UPS is important in synaptic plasticity (Ehlers 2003;Bingol and Sheng, 2011;Li and Man, 2013), including plasticity following retrieval of fear (Lee et al, 2008;Jarome et al, 2011) and drug (Massaly et al, 2013;Ren et al, 2013) memories. However, no studies have examined its role in drug memory retrieval following drug selfadministration or at different times after the last drug exposure.…”

Section: Discussionmentioning

confidence: 99%

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

Werner

Milovanovic

Christian

et al. 2015

Neuropsychopharmacol

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The ubiquitin-proteasome system (UPS) has been implicated in the retrieval-induced destabilization of cocaine-and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self-administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine-and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts.

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Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Cited by 29 publications

References 76 publications

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

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