Protein kinase C regulates <scp>AMPA</scp> receptor auxiliary protein Shisa9/<scp>CKAMP</scp>44 through interactions with neuronal scaffold <scp>PICK</scp>1

Kunde, Stella-Amrei; Rademacher, Nils; Zieger, Hanna L.; Shoichet, Sarah A.

doi:10.1002/2211-5463.12261

Cited by 18 publications

(16 citation statements)

References 52 publications

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“…PICK1 was originally cloned as a protein kinase Cα (PKCα) binding protein found in multiple tissues and organs, most abundantly in the brain, endocrine tissues, and skeletal muscle tissue (Human Proteome atlas). Through the PDZ domain, PICK1 interacts with a number of neurotransmitter receptors, transporters, and enzymes (Figure 7f), where in particular the interactions with the AMPAR [148][149][150][151][152][153][154][155][156][157] and the dopamine transporter (DAT) have received particular attention. Through the PDZ domain, PICK1 interacts with a number of neurotransmitter receptors, transporters, and enzymes (Figure 7f), where in particular the interactions with the AMPAR [148][149][150][151][152][153][154][155][156][157] and the dopamine transporter (DAT) have received particular attention.…”

Section: Targeting the Pdz Domain Of Protein Interacting With C Kinasementioning

confidence: 99%

“…It is highly evolutionarily conserved from invertebrates to humans, which suggests that PICK1 has important biological functions. Through the PDZ domain, PICK1 interacts with a number of neurotransmitter receptors, transporters, and enzymes (Figure f), where in particular the interactions with the AMPAR and the dopamine transporter (DAT) have received particular attention . The BAR domain of PICK1 is a domain that facilitates dimerization of PICK1.…”

Section: Pharmacological Targeting Of Pdz Domainsmentioning

confidence: 99%

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PDZ Domains as Drug Targets

Christensen

Čalyševa

Fernandes

et al. 2019

Advanced Therapeutics

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Protein-protein interactions within protein networks shape the human interactome, which often is promoted by specialized protein interaction modules, such as the postsynaptic density-95 (PSD-95), discs-large, zona occludens 1 (ZO-1) (PDZ) domains. PDZ domains play a role in several cellular functions, from cell-cell communication and polarization, to regulation of protein transport and protein metabolism. PDZ domain proteins are also crucial in the formation and stability of protein complexes, establishing an important bridge between extracellular stimuli detected by transmembrane receptors and intracellular responses. PDZ domains have been suggested as promising drug targets in several diseases, ranging from neurological and oncological disorders to viral infections. In this review, the authors describe structural and genetic aspects of PDZ-containing proteins and discuss the current status of the development of small-molecule and peptide modulators of PDZ domains. An overview of potential new therapeutic interventions in PDZ-mediated protein networks is also provided.

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Section: Targeting the Pdz Domain Of Protein Interacting With C Kinasementioning

confidence: 99%

Section: Pharmacological Targeting Of Pdz Domainsmentioning

confidence: 99%

PDZ Domains as Drug Targets

Christensen

Čalyševa

Fernandes

et al. 2019

Advanced Therapeutics

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“…Structurally, AMPAR binding requires a region downstream of Shisa9 transmembrane domain and the cystine-knot domain is essential for its modulation of AMPAR trafficking and gating [ 345 ]. In addition to PSD95, the cytosolic PDZ-binding domain of Shisa9 binds to several other scaffold proteins, including PSD93, SAP97, SAP102, GRIP1, and PICK1 [ 347 , 348 ]. Disrupting PDZ interactions is enough to phenocopy the effect on AMPAR synaptic localization and transmission of Shisa9 knockout suggesting that at least one of these partners is essential for Shisa9 regulatory function [ 347 ].…”

Section: Shisa6 and 9 (Cystine-knot Ampar Modulating Proteins (Ckamp)mentioning

confidence: 99%

“…Disrupting PDZ interactions is enough to phenocopy the effect on AMPAR synaptic localization and transmission of Shisa9 knockout suggesting that at least one of these partners is essential for Shisa9 regulatory function [ 347 ]. Recently, interaction with PICK1 was shown to bridge Shisa9 with PKC, inducing Shisa9 phosphorylation; PICK1 association requires binding of another N-terminal domain of Shisa9, which is important for its regulation of AMPAR function, suggesting a possible competition between AMPAR and PICK1 [ 348 ]. As PICK1 interaction with PKC is important for its targeting to the membrane, this could provide a mechanism for the membrane targeting of Shisa9/PICK1, followed by a switch of Shisa9 to AMPAR/TARP/PSD95 complexes at the surface.…”

Section: Shisa6 and 9 (Cystine-knot Ampar Modulating Proteins (Ckamp)mentioning

confidence: 99%

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

Bissen

Foss

Acker‐Palmer

2019

Cell. Mol. Life Sci.

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To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, therefore, a key mechanism underlying synaptic plasticity. Intensive research over the last 20 years has revealed the increasing importance of interacting proteins, which accompany AMPA receptors throughout their lifetime and help to refine the temporal and spatial modulation of their trafficking and function. In this review, we discuss the current knowledge about the roles of key partners in regulating AMPA receptor trafficking and focus especially on the movement between the intracellular, extrasynaptic, and synaptic pools. We examine their involvement not only in basal synaptic function, but also in Hebbian and homeostatic plasticity. Included in our review are well-established AMPA receptor interactants such as GRIP1 and PICK1, the classical auxiliary subunits TARP and CNIH, and the newest additions to AMPA receptor native complexes.

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“…MLRs are specialized plasmalemmal microdomains that compartmentalize and modulate synaptic signaling and adaptor proteins essential for synaptogenesis, synaptic plasticity and cognitive function [13,20,42]. Proteomics on MLR fractions revealed a novel association between hippocampal MLRs and the AMPAR adaptor and regulatory protein Shisa9 [43][44][45]. Shisa9 is known to regulate synaptic plasticity and memory formation in the hippocampus [43,44].…”

Section: Discussionmentioning

confidence: 99%

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

Wang

Leem

Podvin

et al. 2020

Preprint

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Background: AD presents with severe neurodegeneration which leads to cognitive deficits and dementia. While many previous approaches focused on targeting amyloid and/or tau, we identified a novel molecular and cellular target that attenuates neurodegeneration in AD which may be exploited as therapeutic targets.Methods: Using immunoblot, microscopic immunofluorescence and proteomic analysis, the current study revealed that PSAPP transgenic mice exhibit decreased hippocampal caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic signaling components. Subcellularly, Cav-1 and full length (fl)-TrkB were significantly decreased in hippocampal MLRs. We thus used viral vector that contains a neuronal-targeted Cav-1 construct using the synapsin promoter (SynCav1) to re-express Cav-1 in PSAPP mice. Effects of SynCav1 on cognition function, hippocampal neuron morphology and ultrastructure were examined at 9 (presymptomatic stage) and 11 month (symptomatic stage) respectively.Results: While PSAPP mice showed significant learning and memory deficits at 9 and 11 months, PSAPP mice that received hippocampal SynCav1 (PSAPP-SynCav1) maintained normal learning and memory at 9 and 11 months respectively. Furthermore, PSAPP-SynCav1 mice showed preserved hippocampal MLR-localized fl-TrkB, synaptic ultrastructure, dendritic arborization and axonal myelin content, all of which occurred independent of reducing amyloid deposit and astrogliosis.Conclusions: While transgenic PSAPP mice exhibit decreased hippocampal expression of the MLR scaffolding protein Cav-1 in the early stage of disease, SynCav1 mitigated neuropathology and cognitive deficits in PSAPP mice. Irrespective of amyloid, our approach targeted neuronal degeneration pathways that may be downstream of amyloid species and/or tau in AD but also other forms of neurodegeneration of different or unknown etiology.

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Protein kinase C regulates AMPA receptor auxiliary protein Shisa9/CKAMP44 through interactions with neuronal scaffold PICK1

Cited by 18 publications

References 52 publications

PDZ Domains as Drug Targets

PDZ Domains as Drug Targets

AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

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