Collapsin Response Mediator Protein 2 and Endophilin2 Coordinate Regulation of AMPA Receptor GluA1 Subunit Recycling

Zhang, Jifeng; Li, Jiong; Yin, Yi‐Chen; Li, Xueling; Jiang, Yuxin; Wang, Yong; Cha, Caihui; Guo, Guoqing

doi:10.3389/fnmol.2020.00128

Cited by 11 publications

(8 citation statements)

References 41 publications

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“…Strikingly, analysis performed using the human phenotype ontology database indicated that proteins identified as being decreased in their phosphorylation state in brains from mice with autophagy deficits are associated with EEG abnormality and seizure onset in humans (Fig 7A). These data, taken together with the fact that about 37% of “cytoskeletal protein binding” proteins identified in Fig 6G are directly involved in endocytosis and trafficking of GLUR1 subunit of AMPARs (CLTC, ANK3, DLG1, DPYSL2, EPB41L1, PPP1R9A, SHANK3 and STXBP5; Leonard et al , 1998; Carroll et al , 1999; Shen et al , 2000, 2020b; Uchino et al , 2006; Wu et al , 2008; Smith et al , 2014; Zhang et al , 2020; Fig 7B), prompted us to speculate that altered GLUR1 trafficking, rather than its direct phosphorylation by PKA is a crucial determinant of neuronal excitability in ATG5 KO neurons. In line with this hypothesis and the data described above (see Fig 6K–M), the colocalization of GLUR1 and postsynaptic density marker PSD95 was increased in cultured neurons lacking ATG5 (Appendix Fig S9G and H).…”

Section: Resultsmentioning

confidence: 99%

Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse

et al. 2022

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Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, by combining mouse models of neuron-specific ATG5 deficiency in either excitatory or inhibitory neurons with quantitative proteomics, high-content microscopy, and live-imaging approaches, we show that autophagy protein ATG5 functions in neurons to regulate cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA-R1, which sequesters the PKA catalytic subunit and diminishes cAMP/PKAdependent phosphorylation of postsynaptic cytoskeletal proteins that mediate AMPAR trafficking. Furthermore, ATG5 deletion in glutamatergic neurons augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

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Section: Resultsmentioning

confidence: 99%

Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse

et al. 2022

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“…After culturing hippocampal neurons for 13 DIV, they were transfected with GFP, GFP-Spastin, and other constructs. After transfection for 48 h, electrophysiology assays were performed as per a previously described method (Zhang et al, 2020 ). Miniature excitatory synaptic currents (mEPSCs) were obtained using whole-cell patch-clamp recordings at 20°C–22°C.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of Spastin Promotes the Surface Delivery and Synaptic Function of AMPA Receptors

Chen

Wang

Cha

et al. 2022

Front. Cell. Neurosci.

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Synaptic plasticity is essential for cognitive functions such as learning and memory. One of the mechanisms involved in synaptic plasticity is the dynamic delivery of AMPA receptors (AMPARs) in and out of synapses. Mutations of SPAST, which encodes SPASTIN, a microtubule-severing protein, are considered the most common cause of hereditary spastic paraparesis (HSP). In some cases, patients with HSP also manifest cognitive impairment. In addition, mice with Spastin depletion exhibit working and associative memory deficits and reduced AMPAR levels. However, the exact effect and molecular mechanism of Spastin on AMPARs trafficking has remained unclear. Here, we report that Spastin interacts with AMPAR, and phosphorylation of Spastin enhances its interaction with AMPAR subunit GluA2. Further study shows that phosphorylation of Spastin can increase AMPAR GluA2 surface expression and the amplitude and frequency of miniature excitatory synaptic currents (mEPSC) in cultured hippocampal neurons. Moreover, phosphorylation of Spastin at Ser210 is crucial for GluA2 surface expression. Phosphorylation of Spastin K353A, which obliterates microtubule-severing activity, also promotes AMPAR GluA2 subunit trafficking to the surface and increases the amplitude and frequency of mEPSCs in cultured neurons. Taken together, our data demonstrate that Spastin phosphorylation promotes the surface delivery of the AMPAR GluA2 subunit independent of microtubule dynamics.

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“…Further, ARHGAP8 was shown to interact with Endophilin A2 to increase EGF receptor endocytosis (Lua & Low, 2005). Endophilin A2 is enriched pre- and postsynaptically and shows direct binding to the GluA1 AMPAR subunit, positively impacting its surface recycling via its interaction with Collapsin response mediator protein 2 (CRMP2) (Chowdhury et al , 2006; Zhang et al , 2020). As both, ARHGAP8 and CRMP2 bind Endophilin A2 via the same subdomain, it stands to reason that they could compete for Endophilin A2 binding, with ARHGAP8 overexpression resulting in dampened synaptic AMPAR levels (Lua & Low, 2005; Zhang et al , 2020).…”

Section: Resultsmentioning

confidence: 99%

Neuronal ARHGAP8 controls synapse structure and AMPA receptor-mediated synaptic transmission

Schmidt,

Inácio,

Ferreira

et al. 2024

Preprint

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The aberrant formation and function of neuronal synapses are recognized as major phenotypes in many cases of neurodevelopmental (NDDs) and -psychiatric disorders (NPDs). A growing body of research has identified an expanding number of susceptibility genes encoding proteins with synaptic function. Here, we present the first brain-focused characterization of a potential new susceptibility gene,ARHAGP8, which encodes a Rho GTPase activating protein (RhoGAP). Accumulating evidence suggests that ARHGAP8 plays a pivotal role in the pathogenesis of NPDs/NDDs. We provide the first evidence for ARHGAP8 as a novel player at excitatory synapses, with its synaptic localisation linked to the presence of the developmentally important NMDA receptor subunit GluN2B. By increasing ARHGAP8 levels in hippocampal neurons to mimic the copy number variant found in a subset of patients, we observed reductions in dendritic complexity and spine volume, accompanied by a significant decrease in synaptic AMPA receptor-mediated transmission. These results suggest that ARHGAP8 plays a role in shaping the morphology and function of excitatory synapses, and prompt further investigation of ARHGAP8 as a candidate gene in NDDs/NPDs.

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Collapsin Response Mediator Protein 2 and Endophilin2 Coordinate Regulation of AMPA Receptor GluA1 Subunit Recycling

Cited by 11 publications

References 41 publications

Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse

Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse

Phosphorylation of Spastin Promotes the Surface Delivery and Synaptic Function of AMPA Receptors

Neuronal ARHGAP8 controls synapse structure and AMPA receptor-mediated synaptic transmission

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