Regulation of glycine receptor diffusion properties and gephyrin interactions by protein kinase C

Specht, Christian G.; Grünewald, Nora; Pascual, Olivier; Rostgaard, Nina; Schwarz, Günter; Triller, Antoine

doi:10.1038/emboj.2011.276

Cited by 82 publications

(107 citation statements)

References 38 publications

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“…The competition between GABA A Rs and GlyRs for an overlapping gephyrinbinding site, as shown here, suggests an interdependence of their clustering as well as their transport to the synapse. Major determinants of the competition would be the ratio of free receptor-binding sites in gephyrin and, among the gephyrinbinding receptor subunits, the gephyrin-binding subunit number within a pentameric receptor and the post-translational modifications of the respective motifs within these subunits 20,41 . Although GABA A R transport remains poorly characterized, GlyRs were shown to be retrogradely co-transported with gephyrin by the dynein motor complex via an interaction of the dynein light chain with the central linker of gephyrin 42 .…”

Section: When Interacting Withmentioning

confidence: 99%

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Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin

et al. 2014

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g-Aminobutyric acid type A and glycine receptors (GABA A Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA A Rs are important drug targets regulated by direct interactions with the scaffolding protein gephyrin. Here we deduce the molecular basis of this interaction by chemical, biophysical and structural studies of the gephyrin-GABA A R a3 complex, revealing that the N-terminal region of the a3 peptide occupies the same binding site as the GlyR b subunit, whereas the C-terminal moiety, which is conserved among all synaptic GABA A R a subunits, engages in unique interactions. Thermodynamic dissections of the gephyrinreceptor interactions identify two residues as primary determinants for gephyrin's subunit preference. This first structural evidence for the gephyrin-mediated synaptic accumulation of GABA A Rs offers a framework for future investigations into the regulation of inhibitory synaptic strength and for the development of mechanistically and therapeutically relevant compounds targeting the gephyrin-GABA A R interaction.

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Section: When Interacting Withmentioning

confidence: 99%

“…It can be assumed that post-translational modifications of these residues modulate the gephyrin-GABA A R affinity, and hence, the residence time at the synapse in a similar manner as reported for the protein kinase C-mediated phosphorylation of GlyR b Ser399 (ref. 41).…”

Section: When Interacting Withmentioning

confidence: 99%

Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin

et al. 2014

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“…The regulation of glycine receptor trafficking by Ca 2+ -dependent processes has been described using elegant single particle tracking approaches (10,50,51). IL-1β can rapidly increase intracellular Ca 2+ in astrocytes and neurons (52,53).…”

Section: Glycine Receptor Trafficking and Channel Properties Modulatementioning

confidence: 99%

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Chirila

Brown

Bishop

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses. Glycine receptors (GlyRs) are structurally related to GABA A receptors and have a similar inhibitory role. Here we report that in the superficial dorsal horn of the spinal cord, glycinergic synapses on inhibitory GABAergic neurons exhibit LTP, occurring rapidly after exposure to the inflammatory cytokine interleukin-1 beta. This form of LTP (GlyR LTP) results from an increase in the number and/or change in biophysical properties of postsynaptic glycine receptors. Notably, formalin-induced peripheral inflammation in vivo potentiates glycinergic synapses on dorsal horn neurons, suggesting that GlyR LTP is triggered during inflammatory peripheral injury. Our results define a previously unidentified mechanism that could disinhibit neurons transmitting nociceptive information and may represent a useful therapeutic target for the treatment of pain.G lycine mediates fast synaptic inhibition throughout the spinal cord, brainstem, and midbrain, controlling normal motor behavior and rhythm generation, somatosensory processing, auditory and retinal signaling, and coordination of reflex responses (1). Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels of the Cys-loop receptor family that together with GABA A receptors (GABA A Rs) dynamically interact with the synaptic scaffold protein gephyrin to form inhibitory synapses (1, 2). In the dorsal horn of the spinal cord, glycinergic synapses are essential for nociceptive and tactile sensory processing both during adaptive and pathological pain states (3-7). However, compared with glutamatergic and GABAergic synapses, little is known about the regulation of their synaptic strength. Several studies have examined glycine receptor trafficking in cultured neurons and in heterologous expression systems (8, 9). Intracellular Ca 2+ appears important in the stabilization of GlyRs at synapses in culture (10), and elevation of intracellular Ca 2+ can also potently increase glycine receptor single channel openings in cultured cells and in heterologous systems (11). However, the modulation of glycinergic synaptic strength in native tissue remains relatively unexplored.Following peripheral injury or inflammation, changes in tactile perception develop, including hyperalgesia (exaggerated pain upon noxious stimulation), allodynia (pain in response to innocuous stimuli), and secondary hyperalgesia (pain spreading beyond the confines of the injure...

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“…It is conceivable that gephyrin scaffolds contain a limited number of binding sites for GlyR [59,25,60]. Further evidence for a dissociation between GlyR and gephyrin clustering dynamics was provided by analyzing the interaction between gephyrin and heat-shock cognate protein 70 (HSc70), a chaperone modulating ubiquitination of its substrates [61].…”

Section: Differences Between Gabaergic and Glycinergic Synapsesmentioning

confidence: 99%

Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA(A) receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA(A) receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA(A) receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapses. AbstractKnowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA A receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA A receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA A receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophinglycoprotein complex to the molecular ...

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Regulation of glycine receptor diffusion properties and gephyrin interactions by protein kinase C

Cited by 82 publications

References 38 publications

Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin

Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

Molecular and functional heterogeneity of GABAergic synapses

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