Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca
            <sup>2+</sup>
            /CaMKII signaling

Patriarchi, Tommaso; Buonarati, Olivia R.; Hell, Johannes

doi:10.15252/embj.201899771

Cited by 56 publications

(47 citation statements)

References 297 publications

(631 reference statements)

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“…Of particular interest is AKAP5 (human AKAP79/rodent AKAP150), a postsynaptic scaffolding protein that integrates an array of plasticity-related ion channels, neurotransmitter receptors, scaffolding, and signaling proteins. These include PKA, PKC, several adenylate cyclase (AC) isoforms, the phosphatase CaN, the scaffolding proteins PSD-95 and SAP97, as well as the L-type Ca 2+ channel Ca V 1.2 (see Sanderson and Dell’Acqua, 2011; Woolfrey and Dell’Acqua, 2015; Patriarchi et al, 2018; Figure 3). AKAP5 was identified as a palmitoylated postsynaptic protein in a proteomic study (Kang et al, 2008).…”

Section: Palmitoylation Of Scaffold Proteinsmentioning

confidence: 99%

“…Palmitoylation of A-kinase anchoring protein 5 (AKAP5). Shown are AKAP5 palmitoylation sites (orange shading) within the N-terminal polybasic regions A and C in relation to known binding sites for AKAP5 associated proteins (reviewed in Sanderson and Dell’Acqua, 2011; Woolfrey and Dell’Acqua, 2015; Patriarchi et al, 2018). Residue numbering refers to human AKAP5.…”

Section: Palmitoylation Of Scaffold Proteinsmentioning

confidence: 99%

“…This hypothesis is consistent with the observation that changing PSD-95 palmitoylation in PSDs altered PSD-95 and AMPAR but not NMDAR levels (Jeyifous et al, 2016), and that AMPAR nanodomains were lost while NMDAR nanodomains were preserved upon PSD-95 knockdown (Chen et al, 2011). Adopting an extended conformation likely also contributes to binding of PSD-95 to stargazin and potentially other TARPs, whose C-termini also undergo an extension away from the plasma membrane upon their phosphorylation by CaMKII (Hafner et al, 2015), which is an important molecular component of synaptic plasticity (Hell, 2014; Patriarchi et al, 2018).…”

Section: The Role Of Psd-95 Palmitoylation In Synaptic Plasticitymentioning

confidence: 99%

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Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

Matt

Kim

Chowdhury

et al. 2019

Front. Mol. Neurosci.

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Many postsynaptic proteins undergo palmitoylation, the reversible attachment of the fatty acid palmitate to cysteine residues, which influences trafficking, localization, and protein interaction dynamics. Both palmitoylation by palmitoyl acyl transferases (PAT) and depalmitoylation by palmitoyl-protein thioesterases (PPT) is regulated in an activity-dependent, localized fashion. Recently, palmitoylation has received attention for its pivotal contribution to various forms of synaptic plasticity, the dynamic modulation of synaptic strength in response to neuronal activity. For instance, palmitoylation and depalmitoylation of the central postsynaptic scaffold protein postsynaptic density-95 (PSD-95) is important for synaptic plasticity. Here, we provide a comprehensive review of studies linking palmitoylation of postsynaptic proteins to synaptic plasticity.

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Section: Palmitoylation Of Scaffold Proteinsmentioning

confidence: 99%

Section: Palmitoylation Of Scaffold Proteinsmentioning

confidence: 99%

Section: The Role Of Psd-95 Palmitoylation In Synaptic Plasticitymentioning

confidence: 99%

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Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

Matt

Kim

Chowdhury

et al. 2019

Front. Mol. Neurosci.

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“…The sequence-diverse AMPAR C-terminal domains (CTDs) have multiple phosphorylation and interaction sites for cytosolic proteins (Fig. 1b, 2a) 20 , and were central to previous synaptic anchoring models 21,22 . The GluA2 CTD interacts with NSF (N-ethylmaleimide sensitive fusion protein) and the scaffolding proteins GRIP1/ABP and PICK1, with suggested roles in both surface delivery and synaptic anchoring, while the GluA1 CTD interacts with SAP97 21,22 .…”

Section: Introductionmentioning

confidence: 99%

AMPA receptor anchoring at CA1 synapses is determined by an interplay of N-terminal domain and TARP γ8 interactions

Watson

Striessnig

et al. 2020

Preprint

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AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission. Changes in AMPAR localisation can enact synaptic plasticity, allowing long-term information storage, and is therefore tightly controlled. Multiple mechanisms regulating AMPAR synaptic anchoring have been described, but with limited coherence or comparison between reports, our understanding of this process is unclear. Here, combining synaptic recordings and super-resolution imaging, we compare the contributions of three AMPAR interaction domains controlling transmission at hippocampal CA1 synapses. We show that the AMPAR C-termini play only a modulatory role, whereas the extracellular N-terminal domain (NTD) and PDZ interactions of the auxiliary subunit TARP γ8 are both crucial, and each is sufficient to maintain transmission. Our data support a model in which γ8 accumulates AMPARs at the postsynaptic density, where the NTD further tunes their positioning. This interplay between cytosolic (γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity.

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“…For example, AKAP79/150 localizes PKA and CaN for phospho-regulation of AMPAR and L-type Ca 2+ channels (105). Hypothetically, Cav2.…”

Section: Discussionmentioning

confidence: 99%

R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites

Murphy

Gutzmann

Lin

et al. 2020

Preprint

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15The transient voltage-gated K + current (IA) mediated by Kv4.2 in CA1 hippocampal pyramidal 16 neurons regulates dendritic excitability, synaptic plasticity, and learning. Here we report that Ca 2+ 17 entry mediated by the voltage-gated Ca 2+ channel subunit Cav2.3 regulates Kv4.2 function in CA1 18 pyramidal neurons through Ca 2+ binding auxiliary subunits known as K + channel interacting 19 proteins (KChIPs). We characterized an interaction between Cav2.3 and Kv4.2 using 20 immunofluorescence colocalization, coimmunoprecipitation, electron microscopy, FRAP, and 21 FRET. We found that Ca 2+ -entry via Cav2.3 increases Kv4.2-mediated whole-cell current due in 22 part to an increase in Kv4.2 surface expression. In hippocampal neurons, pharmacological block 23 of Cav2.3 reduced whole-cell IA. We also found reduced IA in Cav2.3 knockout mouse neurons 24 with a loss of the dendritic IA gradient. Furthermore, the Cav2.3-Kv4.2 complex was found to 25 regulate the size of synaptic currents and spine Ca 2+ transients. These results reveal an 26 intermolecular Cav2.3-Kv4.2 complex impacting synaptic integration in CA1 hippocampal 27 neurons. 28 29 30 31 32 33 34 93 and Kv4.2 that regulates Kv4.2 function by a novel mechanism. 94 95 96 97 98 99 100 101 4 RESULTS 102 103 Cav2.3 and Kv4.2 form an ion channel complex in hippocampal neurons 104The characteristic kinetics of neuronal IA requires expression of KChIP and DPP 105 accessory subunits that had been identified and described nearly two decades ago (27, 28). In 106 an effort to identify novel Kv4.2 protein interactions and modifying enzymes in hippocampal 107 neurons we used tandem affinity purification (TAP) and protein identification with mass 108 spectrometry (MS) (58). As expected, Kv4.2 pulled down Kv4.1, Kv4.2, Kv4.3, and previously 109 described auxiliary subunits (DPPs and KChIPs) confirming the specificity of the assay (Figure 1110 -Figure supplement 1A). In addition to known binding partners, we also identified peptides 111 representing a significant proportion of the Cav2.3 amino acid sequence (Figure 1 -Figure 112 supplement 1B,C). Cav2.3 was the only voltage-gated Ca 2+ channel identified in this screen.113 To confirm the presence of a hippocampal Cav2.3 and Kv4.2 molecular complex we 114 carried out several immunological measurements using hippocampal tissue. Broad neuropil 115 colocalization of endogenous Cav2.3 and Kv4.2 immunofluorescent signal was consistent with 116 enrichment in the dendrite layers of the hippocampus as has been previously reported for each 117 channel separately (Figure 1A) (51, 59). Both Cav2.3 and Kv4.2 are also known to be expressed 118 in dendrites and spines. To evaluate Cav2.3-Kv4.2 colocalization, we transfected cultured 119 hippocampal neurons with Cav2.3-GFP (i), Kv4.2-myc (ii), and mCherry (iii) plasmids (Figure 1B). 120In addition to immunofluorescent colocalization in dendrites, both channels were enriched in 121 spines when compared to the free cytosolic mCherry fluorescent protein (Figure 1C,D). 122Immunofluorescent...

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Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

Cited by 56 publications

References 297 publications

Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

AMPA receptor anchoring at CA1 synapses is determined by an interplay of N-terminal domain and TARP γ8 interactions

R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites

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Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

Cited by 56 publications

References 297 publications

Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

AMPA receptor anchoring at CA1 synapses is determined by an interplay of N-terminal domain and TARP γ8 interactions

R-type voltage-gated Ca2+channels mediate A-type K+current regulation of synaptic input in hippocampal dendrites

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Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

R-type voltage-gated Ca²⁺channels mediate A-type K⁺current regulation of synaptic input in hippocampal dendrites