GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling

Shin, Seung-Soo; Zhang, Nanyan; Hansen, Jonathan D; Gerges, Nashaat Z.; Pak, Daniel T.S.; Sheng, Morgan; Lee, S.H.

doi:10.1038/nn.3259

Cited by 119 publications

(146 citation statements)

References 51 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…3). GKAP phosphorylation by CaMKIIa on Ser54 promotes its removal from synaptic sites, polyubiquitination and subsequent degradation by the proteasome (Shin et al, 2012). All these synaptic proteins and others (e.g.…”

Section: Role Of Ups In Nervous Systemmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

114

View full text Add to dashboard Cite

A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

show abstract

Section: Role Of Ups In Nervous Systemmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

114

View full text Add to dashboard Cite

show abstract

“…Second, TRIM3 may control GA-BA-A receptor trafficking and inhibitory synaptic transmission in cortical neurons (Cheung et al, 2010). Finally, TRIM3 was shown to reduce the levels of postsynaptic scaffold proteins GKAP and SHA NK1 and alter spine morphology in hippocampal neurons in vitro (Hung et al, 2010); however, activity-dependent removal of GKAP from synapses in vivo does not appear to depend on TRIM3 (Shin et al, 2012). Importantly, none of these studies investigated the direct effects of TRIM3 deficiency on synaptic protein levels, synaptic plasticity, or learning and memory in vivo.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

Schreiber¹,

Végh²,

Dawitz³

et al. 2015

J Exp Med

View full text Add to dashboard Cite

“…This effect is not due to AMPA-induced dopamine release [155]. As AMPA is an artificial agonist that stimulates a specific class of ionotropic glutamate receptor, endogenous glutamate released in this region would also stimulate NMDA-type receptors, which removes SAPAPs from the synapse [138]. In the dorsal mPFC, all SAPAPs were significantly reduced in animals sensitized to cocaine and acutely exposed on test day.…”

Section: Discussionmentioning

confidence: 96%

“…While their exact functions in addition to receptor clustering are not known, SAPAPs (also called DAP, or GKAP in older literature) also interacts with dynein in spindle formation [136], can recruit nNOS to the post synaptic density [137], and can be removed from the synaptic density due to increased excitatory activity [138]. SAPAPs also seem to be localized exclusively with cholinergic/glutamatergic synapses, and show differential expression spatially, with SAPAP3 being restricted to the dendrite and all others to the soma [139].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, electrical stimulation enhances the locomotor effects of behavioral sensitization by stimulation of NMDA receptors ("kindling") [146], and activation also uncouples them from SAPAPs [138]. Even though these results are seemingly in conflict with one another, they are evidence that the dorsal and ventral mPFC have differing roles in the sensitization process that can be understood by examining how these regions act in concert with each other.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

Summers¹

View full text Add to dashboard Cite

DEDICATIONTo my mother Andrea, who through her example taught me that the values of hard work, integrity, and good manners never go out of style To Karen, who taught me the true meaning of courage under the threat of certain death, and that those no longer with us physically continue to live in our thoughts iv ACKNOWLEDGEMENTS All information and data in this text was only possible due to the generous support and inexhaustible patience of my advisor Jeff Steketee and my graduate committee (which included Drs. John Boughter, Michael McDonald, Kazuko Sakata, and Wen Lin Sun). Also, instrumental to the completion of this project were the helping hands of Dr. Steve Tavalin. This project also could have never been completed without financial support from the University of Tennessee Health Science Center Neuroscience Institute and the National Institute on Drug Abuse (NIDA).v ABSTRACT Towards the goal of improving the knowledge base of how drugs of abuse function to create addicts and using currently uninvestigated areas of this knowledge base, we focused our research studies the male albino rat, and strived to explain how cocaine sensitization alters particular molecular mechanisms in the mesocorticolimbic system related to glutamate receptors, SAPAPs, and affects drug self-administration. Taking all the previously discussed research studies into consideration, we hypothesized that low-dose cocaine self-administration would yield a significant elevation in drug seeking behavior for psychostimulant sensitized animals. For specific changes at the PSD, we hypothesized that acute cocaine exposure and/or cocaine sensitization would alter iGluRs levels in the mPFC, and SAPAP levels in multiple sites of the mesocorticolimbic system. To test these hypotheses, we investigated the effects of psychostimulant sensitization on various parameters of self-administration by infusing a low-dose cocaine reward proven to not induce sensitization during self-administration (reported here as 0.3 mg/kg/infusion). Although drug exposure did not significantly alter self-administration behavior, we did find that more drug exposed subjects acquired selfadministration behavior when compared to drug naïve controls. We also investigated the effects of acute cocaine exposure and/or cocaine sensitization on iGluRs in the mPFC and SAPAPs in the entire mesocorticolimbic circuit thru western blotting, immunolabeling of proteins of interest, and comparing protein levels to those found in cocaine naïve controls. A limited self-administration protocol also tested if SAPAP levels were altered by self-administration of a low-dose cocaine reward. For these experiments, we found that SAPAP protein levels are altered in multiple regions of the mesocorticolimbic system in response to contingent and non-contingent cocaine exposure, and that iGluR receptor subunits are altered in the prefrontal cortex in response to non-contingent cocaine exposure. vi PREFACEThe Incans that first cultivated the coca plant for medicinal use five millennia ago reserved this "Elix...

show abstract

GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling

Cited by 119 publications

References 51 publications

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

Contact Info

Product

Resources

About