Editorial: role of protein palmitoylation in synaptic plasticity and neuronal differentiation

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Yoshii, A., & Green, W. N. Editorial: role of protein palmitoylation in synaptic plasticity and neuronal differentiation. Frontiers in Synaptic Neuroscience, 12(27), (2020), doi:10.3389/fnsyn.2020.00027.Protein palmitoylation, the reversible addition of palmitate to proteins, is a dynamic post-translational modification. Both membrane (e.g., channels, transporters, and receptors) and cytoplasmic proteins (e.g., cell adhesion, scaffolding, cytoskeletal, and signaling molecules) are substrates. In mammals, palmitoylation is mediated by 23-24 palmitoyl acyltransferases (PATs), also called ZDHHCs for their catalytic aspartate-histidine-histidine-cysteine (DHCC) domain. PATs are integral membrane proteins found in cellular membranes. In the palmitoylation cycle, palmitate is removed by the depalmitoylation enzymes, acyl palmitoyl transferases (APT1 and 2), and α/β Hydrolase domain-containing protein 17 (ABHD17A-C). These are cytoplasmic proteins that are targeted to membranes where they are substrates for PATs. The second class of depalmitoylating enzymes are palmitoyl thioesterases, PPT1 and 2, discovered through their association with infantile neuronal ceroid lipofuscinosis. These are secreted proteins found in the lumen of intracellular organelles, primarily lysosomes, where their function as depalmitoylating enzymes is unclear.This work was supported by University of Illinois start-up fund (to AY) and NIH/NIDA (grant DA044760 to WG)

CASK regulates SAP97 conformation and its interactions with AMPA and NMDA receptors

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Neuroscience 33 (2013): 12067-12076, doi:10.1523/JNEUROSCI.0816-13.2013.SAP97 interacts with AMPA receptors (AMPARs) and NMDA receptors (NMDARs) during sorting and trafficking to synapses. Here we addressed how SAP97 distinguishes between AMPARs and NMDARs and what role the adaptor/scaffold protein, CASK, plays in the process. Using intramolecular SAP97 Förster resonance energy transfer sensors, we demonstrated that SAP97 is in “extended” or “compact” conformations in vivo. SAP97 conformation was regulated by a direct interaction between SAP97 and CASK through L27 protein-interaction domains on each protein. Unbound SAP97 was mostly in the compact conformation, while CASK binding stabilized it in an extended conformation. In HEK cells and rat hippocampal neurons, SAP97 in the compact conformation preferentially associated and colocalized with GluA1-containing AMPARs, and in the extended conformation colocalized with GluN2B-containing NMDARs. Altogether, our findings suggest a molecular mechanism by which CASK binding regulates SAP97 conformation and its subsequent sorting and synaptic targeting of AMPARs and NMDARs during trafficking to synapses.This work was supported by the U.S. National Institutes of Health (NIH) under grant numbers NS043782, MH081251, and DA019695 (W.N.G.). This project was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 RR024999 (O.J.) and faculty fellowships from the Marine Biological Laboratory.2014-01-1

William N. Green requesting a certified copy of discharge for Patrick Bisber

https://digitalmaine.com/arc_me_militia/1128/thumbnail.jp

Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in eLife 4 (2015): e06878, doi:10.7554/eLife.06878.Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites.This work was supported by the U.S. National Institutes of Health under grant numbers NS043782, NS090903 and DA035430 (WNG). This project was also supported by the University of Chicago, Department of Neurobiology Erma Smith Scholarship from the Physiology Endowment Fund and faculty fellowships to WNG and JMM from the Marine Biological Laboratory

Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. Here we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites

Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in eLife 6 (2017): e25651, doi:10.7554/eLife.25651.To better understand smoking cessation, we examined the actions of varenicline (Chantix) during long-term nicotine exposure. Varenicline reduced nicotine upregulation of α4β2-type nicotinic receptors (α4β2Rs) in live cells and neurons, but not for membrane preparations. Effects on upregulation depended on intracellular pH homeostasis and were not observed if acidic pH in intracellular compartments was neutralized. Varenicline was trapped as a weak base in acidic compartments and slowly released, blocking 125I-epibatidine binding and desensitizing α4β2Rs. Epibatidine itself was trapped; 125I-epibatidine slow release from acidic vesicles was directly measured and required the presence of α4β2Rs. Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic vesicles containing α4β2Rs. We conclude that varenicline as a smoking cessation agent differs from nicotine through trapping in α4β2R-containing acidic vesicles that is selective and nicotine-regulated. Our results provide a new paradigm for how smoking cessation occurs and suggest how more effective smoking cessation reagents can be designed.This work was supported by National Institutes of Health RO1DA 035430 and a Pilot Project from the University of Chicago Can- cer Center

In Memoriam: Memorial Tributes for Professor Elizabeth B. Clark

Today we come together to remember Professor Elizabeth Battelle Clark, Betsy to all who knew her. We were shocked to hear of her illness, inspired by the intensity of her fight against it, and deeply saddened by her death. We have come together before to mourn her loss. Now we gather once more to celebrate our good fortune to have known Betsy and to share our remembrances of her