Membrane palmitoylated protein 2 is a synaptic scaffold protein required for synaptic SK2-containing channel function

Kim, Gukhan; Luján, Rafael; Schwenk, Jochen M.; Kelley, Melissa H.; Aguado, Carolina; Watanabe, Masahiko; Fakler, Bernd; Maylie, James; Adelman, John P.

doi:10.7554/elife.12637

Cited by 20 publications

(20 citation statements)

References 44 publications

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“…Additionally, MPP2 has two L27 domains at its N-terminus that are known to be involved in heterodimerisation with other L27 domain-containing proteins 25 , and may be responsible for the homomultimerisation properties that we observe in MPP2. Recent proteomic studies highlighted a putative role for MPP2 in neurons 20 , and during the course of this study, a functional interaction between MPP2 and potassium channels was described 26 ; however, a direct link between MPP2 and associated transmembrane PDZ ligands has not been previously investigated in the context of the synapse. Our findings that MPP2 interacts directly with the C-terminus of SynCAM1 are in line with previous reports that MPP family proteins are able to bind to SynCAM family members in epithelial cells 27 28 29 and open new avenues for investigation into the unknown functions of MPP2 at synaptic sites.…”

Section: Discussionmentioning

confidence: 79%

MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density

Rademacher

Schmerl

Lardong

et al. 2016

Sci Rep

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At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons. MPP2 also colocalises with the synaptic adhesion molecule SynCAM1. We demonstrate that the SynCAM1 C-terminus interacts directly with the MPP2 PDZ domain and that MPP2 does not interact in this manner with other highly abundant postsynaptic transmembrane proteins. Our results highlight a previously unexplored role for MPP2 at postsynaptic sites as a scaffold that links SynCAM1 cell adhesion molecules to core proteins of the postsynaptic density.

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Section: Discussionmentioning

confidence: 79%

MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density

Rademacher

Schmerl

Lardong

et al. 2016

Sci Rep

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“…Recently, MPP2 was found to interact also with guanylate kinase-associated protein (GKAP) and the synaptic cell adhesion molecule (SynCAM1) 1, a protein also involved in structuring PSDs [249]. MPP2 also interacts with small conductance-activated potassium SK2 channels and positions them properly at the synapse, a crucial element for their role in synaptic plasticity [250]. A similar role for AMPARs is open for investigation.…”

Section: Pdz Domain-containing Interactantsmentioning

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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“…Our data revealed that mice exposed to maternal separation presented a significant expression downregulation of the spinal membrane SK2 channel protein and SK2-mediated I AHP . Synaptic SK2-containing channels can modulate the induction of synaptic plasticity and excitatory postsynaptic responses, due to the activation by synaptically evoked Ca 2+ influx [ 38 ]. Our study indicated that the downregulation of the membrane SK2 channel protein expression contributed to an elevation of neuronal excitability which was validated by an increase in neuronal firing rates in spinal DH.…”

Section: Discussionmentioning

confidence: 99%

“…MPP2 is a novel synaptic scaffold, which is localized in postsynaptic sites in hippocampal neurons by binding to the abundant postsynaptic scaffold proteins such as PSD-95 and guanylate kinase-associated protein (GKAP) [ 61 ]. Moreover, MPP2 has been recently demonstrated to be responsible for proper synaptic localization and function of SK2-containing channels in hippocampal CA1 pyramidal neurons [ 38 ]. In our study, coimmunoprecipitation findings affirmed that MPP2 could interact with SK2 in the spinal cord DH, along with a decrease in the membrane MPP2 protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the localization of SK2 channels on the cell surface membrane can be dynamically governed by the anterograde and retrograde trafficking [ 37 ]. Recently, a novel synaptic scaffold MPP2 has been reported to be responsible for locating the SK2 channel at the synapses, which allows SK2 channels to contribute to long-term potentiation (LTP) and synaptic plasticity fortification [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

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Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

Gao

Hua

et al. 2020

Neural Plasticity

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Background. Visceral hypersensitivity is a common occurrence of gastrointestinal diseases such as irritable bowel syndrome (IBS), wherein early-life stress (ELS) may have a high predisposition to the development of visceral hypersensitivity in adulthood, with the specific underlying mechanism still elusive. Herein, we assessed the potential effect of small-conductance calcium-activated potassium channel subtype 2 (SK2) in the spinal dorsal horn (DH) on the pathogenesis of visceral hypersensitivity induced by maternal separation (MS) in mice. Methods. Neonatal mice were subjected to the MS paradigm, an established ELS model. In adulthood, the visceral pain threshold and the abdominal withdrawal reflex (AWR) were measured with an inflatable balloon. The elevated plus maze, open field test, sucrose preference test, and forced swim test were employed to evaluate the anxiety- and depression-like behaviors. The expression levels of SK2 in the spinal DH were determined by immunofluorescence and western blotting. The mRNA of SK2 and membrane palmitoylated protein 2 (MPP2) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Electrophysiology was applied to evaluate the neuronal firing rates and SK2 channel-mediated afterhyperpolarization current (IAHP). The interaction between MPP2 and SK2 was validated by coimmunoprecipitation. Results. In contrast to the naïve mice, ethological findings in MS mice revealed lowered visceral pain threshold, more evident anxiety- and depression-like behaviors, and downregulated expression of membrane SK2 protein and MPP2 protein. Moreover, electrophysiological results indicated increased neuronal firing rates and decreased IAHP in the spinal DH neurons. Nonetheless, intrathecal injection of the SK2 channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) in MS mice could reverse the electrophysiological alterations and elevate the visceral pain threshold. In the naïve mice, administration of the SK2 channel blocker apamin abated IAHP and elevated spontaneous neuronal firing rates in the spinal DH neurons, reducing the visceral pain threshold. Finally, disruption of the MPP2 expression by small interfering RNA (siRNA) could amplify visceral hypersensitivity in naïve mice. Conclusions. ELS-induced visceral pain and visceral hypersensitivity are associated with the underfunction of SK2 channels in the spinal DH.

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Membrane palmitoylated protein 2 is a synaptic scaffold protein required for synaptic SK2-containing channel function

Cited by 20 publications

References 44 publications

MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density

MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density

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

Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

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