scholarly journals Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor

2019 ◽  
Author(s):  
Sanghyeon Lee ◽  
Sunha Park ◽  
Hyojin Lee ◽  
Seulki Han ◽  
Jae-man Song ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
E3 Ligase ◽  
Surface Expression ◽  
Mapk Signaling ◽  
Post Translational Modification ◽  
Excitatory Neurotransmitter ◽  
Metabotropic Glutamate ◽  
Ubiquitin E3 Ligase ◽  
Beta Arrestins ◽  
And Function

AbstractThe metabotropic glutamate receptor 7 (mGlu7) is a class C G protein-coupled receptor (GPCR) that modulates excitatory neurotransmitter release at the presynaptic active zone. Although post-translational modification of cellular proteins with ubiquitin is a key molecular mechanism governing protein degradation and function, mGlu7 ubiquitination and its functional consequences have not been elucidated yet. Here, we report that Nedd4 ubiquitin E3 ligase and β-arrestins regulate ubiquitination of mGlu7 in heterologous cells and neurons. Upon agonist-stimulation, β-arrestins recruit Nedd4 to mGlu7 and facilitate Nedd4-mediated ubiquitination of mGlu7. Nedd4 and β-arrestins regulate constitutive and agonist-induced endocytosis of mGlu7 and are required for mGlu7-dependent MAPK signaling in neurons. In addition, Nedd4-mediated ubiquitination results in the degradation of mGlu7 by both the lysosomal and proteasomal degradation pathways. These findings provide a model in which Nedd4 and β-arrestin act together as a complex to regulate mGlu7 surface expression and function at the presynaptic terminals.

scholarly journals Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Sanghyeon Lee ◽  
Sunha Park ◽  
Hyojin Lee ◽  
Seulki Han ◽  
Jae-man Song ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Surface Expression ◽  
Degradation Pathway ◽  
Mapk Signaling ◽  
Post Translational Modification ◽  
Excitatory Neurotransmitter ◽  
Ubiquitin E3 Ligase ◽  
And Function

The metabotropic glutamate receptor 7 (mGlu7) is a class C G protein-coupled receptor that modulates excitatory neurotransmitter release at the presynaptic active zone. Although post-translational modification of cellular proteins with ubiquitin is a key molecular mechanism governing protein degradation and function, mGlu7 ubiquitination and its functional consequences have not been elucidated yet. Here, we report that Nedd4 ubiquitin E3 ligase and β-arrestins regulate ubiquitination of mGlu7 in heterologous cells and rat neurons. Upon agonist stimulation, β-arrestins recruit Nedd4 to mGlu7 and facilitate Nedd4-mediated ubiquitination of mGlu7. Nedd4 and β-arrestins regulate constitutive and agonist-induced endocytosis of mGlu7 and are required for mGlu7-dependent MAPK signaling in neurons. In addition, Nedd4-mediated ubiquitination results in the degradation of mGlu7 by both the ubiquitin-proteasome system and the lysosomal degradation pathway. These findings provide a model in which Nedd4 and β-arrestin act together as a complex to regulate mGlu7 surface expression and function at presynaptic terminals.

scholarly journals LRIT3 is required for nyctalopin expression and normal ON and OFF pathway signaling in the retina

2018 ◽  
Author(s):  
Nazarul Hasan ◽  
Gobinda Pangeni ◽  
Thomas A. Ray ◽  
Kathryn M. Fransen ◽  
Jennifer Noel ◽  
...  
Keyword(s):  
Visual Function ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Release ◽  
Electrode Array ◽  
Light Response ◽  
Photoreceptor Cells ◽  
Sole Source ◽  
Bipolar Cells ◽  
Metabotropic Glutamate ◽  
And Function

ABSTRACTAt its first synapse, the retina establishes two parallel channels that encode light increments (ON) or decrements (OFF). At the same synapse, changes in photoreceptor glutamate release are sensed by ON bipolar cells (BCs) via the metabotropic glutamate receptor 6 (mGluR6), and OFF BCs via ionotropic BCs, which differ in their synaptic configuration with the photoreceptor terminal. ON BCs form invaginating synapses that bring them in close proximity to presynaptic ribbons and the presumed sole source of glutamate release. OFF bipolar cells form flat contacts distal to the ribbon synapse. We investigated the role of LRIT3 in normal assembly and function of the mGlur6 signaling cascade present in ON BCs. We demonstrate that LRIT3 is required for nyctalopin expression and thus TRPM1 expression and function. Using glutamate imaging, whole-cell electrophysiology, and multi-electrode array extracellular recordings we demonstrate that the loss of LRIT3 impacts both the ON and OFF pathways at the level of the BCs. The effect on ON pathway signaling, a lack of ON BC response, is shared by mutants lacking mGluR6, TRPM1 GPR179 or nyctalopin. The effects on the OFF pathway are unique to LRIT3, and include a decrease in response amplitude of both OFF BC and GCs. Based on these results, we propose a working model where LRIT3 is required for either efficient glutamate release or reuptake from the first retinal synapse.SIGNIFICANCE STATEMENTAt the first visual synapse, photoreceptor cells signal to two distinct bipolar cell (BC) populations, one characterized by a depolarizing response to light onset (ON or DBCs), the other by a hyperpolarizing response (OFF or HBCs). The DBC light response depends on a G protein-coupled receptor and associated protein complex, known as the signalplex. Mutations in signalplex proteins lead to DBC pathway-specific loss of visual function. Here we show how loss of LRIT3, a previously identified signalplex protein, prevents functional assembly of the DBC signalplex and alters visual function in both ON and OFF signaling pathways. Thus, our results indicate that the function of LRIT3 at this first synapse extends beyond assembly of the DBC signalplex.

scholarly journals CENP-B dynamics at centromeres is regulated by a SUMOylation/ubiquitination and proteasomal-dependent degradation mechanism involving the SUMO-targeted ubiquitin E3 ligase RNF4

2018 ◽  
Author(s):  
Jhony El Maalouf ◽  
Pascale Texier ◽  
Indri Erliandri ◽  
Camille Cohen ◽  
Armelle Corpet ◽  
...  
Keyword(s):  
Dna Binding ◽  
Degradation Mechanism ◽  
E3 Ligase ◽  
Major Constituent ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Ubiquitin E3 Ligase ◽  
Satellite Repeats ◽  
Histone H3 Variant ◽  
Centromeric Protein

AbstractCentromeric protein B (CENP-B) is a major constituent of the centromere. It is a DNA binding protein that recognizes a specific 17-nt sequence present in the centromeric alphoid satellite repeats. CENP-B importance for centromere stability has only been revealed recently. In addition to its DNA binding properties, CENP-B interacts with the histone H3 variant CENP-A and CENP-C. These interactions confer a mechanical strength to the kinetochore that enables accurate sister chromatids segregation to avoid aneuploidy. Therefore, understanding the mechanisms that regulate CENP-B stability at the centromere is a major unresolved issue for the comprehension of centromere function. In this study, we demonstrate that lysine K402 of CENP-B is a substrate for SUMO post-translational modifications. We show that K402 regulates CENP-B stability at centromeres through a SUMOylation/ubiquitination and proteasomal-dependent degradation mechanism involving the SUMO-Targeted Ubiquitin E3 Ligase RNF4/SNURF. Our study describes SUMOylation of CENP-B as a major post-translational modification involved in centromere dynamics.

scholarly journals Structural Diversity of Ubiquitin E3 Ligase

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6682
Author(s):  
Sachiko Toma-Fukai ◽  
Toshiyuki Shimizu
Keyword(s):  
E3 Ligase ◽  
Structural Diversity ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Ubiquitin Ligase E3 ◽  
Ubiquitin Conjugating Enzyme

The post-translational modification of proteins regulates many biological processes. Their dysfunction relates to diseases. Ubiquitination is one of the post-translational modifications that target lysine residue and regulate many cellular processes. Three enzymes are required for achieving the ubiquitination reaction: ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). E3s play a pivotal role in selecting substrates. Many structural studies have been conducted to reveal the molecular mechanism of the ubiquitination reaction. Recently, the structure of PCAF_N, a newly categorized E3 ligase, was reported. We present a review of the recent progress toward the structural understanding of E3 ligases.

Glutamate and Depression

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
F. Kapsali ◽  
C. Tsopelas ◽  
I. Kamilaris ◽  
M. Dimitraka ◽  
A. Sardis
Keyword(s):  
Ampa Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Antidepressant Activity ◽  
Brain Regions ◽  
Nmda Antagonists ◽  
Genetic Studies ◽  
Excitatory Neurotransmitter ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Promising Target

Glutamate is the principal excitatory neurotransmitter in the cerebral cortex and it is implicated in the pathophysiology of depression and antidepressant activity.Aim:Aim of this study is to review recent studies and examine the physiology of glutamate and its receptors, pathophysiology of NMDA, effects of stress on glial cells and glutamate neurotransmission and explore the antidepressant properties of NMDA antagonists.Method:Review of recent pharmacological, imaging and genetic studies.Results:Increasing evidence supports a tight relationship between stress, the glutamatergic system and depression. Extracellular glutamate concentrations are increased in several brain regions including prefrontal cortex and hippocampus after exposure to stress. Interactions between glutamate and other neurotransmitters are discussed, as are possible mechanisms by which such altered receptor activity might result in the clinical expression of depression.A variety of NMDA antagonists, group I metabotropic glutamate receptor antagonists, as well as positive modulators of AMPA receptors, demonstrate efficacy in various preclinical modelsConclusions:It seems that a breakthrough in the therapy of depression will require going beyond monoamine-based theory of depression. Evidence indicates that the glutaminergic system might be a promising target fir novel antidepressant therapy.

scholarly journals Surface expression of metabotropic glutamate receptor variants mGluR1a and mGluR1b in transfected HEK293 cells

2008 ◽  
Vol 55 (4) ◽  
pp. 409-418 ◽  
Author(s):  
Jiri Kumpost ◽  
Zdenka Syrova ◽  
Lenka Kulihova ◽  
Daniela Frankova ◽  
Jean-Charles Bologna ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Surface Expression ◽  
Hek293 Cells ◽  
Metabotropic Glutamate

scholarly journals Corequirement of PICK1 Binding and PKC Phosphorylation for Stable Surface Expression of the Metabotropic Glutamate Receptor mGluR7

Neuron ◽  
2008 ◽  
Vol 58 (5) ◽  
pp. 736-748 ◽  
Author(s):  
Young Ho Suh ◽  
Kenneth A. Pelkey ◽  
Gabriela Lavezzari ◽  
Paul A. Roche ◽  
Richard L. Huganir ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Surface Expression ◽  
Metabotropic Glutamate ◽  
Stable Surface

scholarly journals Metabotropic Glutamate Receptor Trafficking and its Role in Drug-Induced Neurobehavioral Plasticity

2021 ◽  
pp. 1-16
Author(s):  
Peter U. Hámor ◽  
Marek Schwendt
Keyword(s):  
Glutamate Receptor ◽  
Membrane Trafficking ◽  
Metabotropic Glutamate Receptor ◽  
Neuropsychiatric Disorders ◽  
Surface Expression ◽  
Receptor Trafficking ◽  
Fine Tuning ◽  
Cell Surface Expression ◽  
Metabotropic Glutamate ◽  
Glutamate Receptor Trafficking

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system that guides developmental and experience-dependent changes in many cellular substrates and brain circuits, through the process collectively referred to as neurobehavioral plasticity. Regulation of cell surface expression and membrane trafficking of glutamate receptors represents an important mechanism that assures optimal excitatory transmission, and at the same time, also allows for fine-tuning neuronal responses to glutamate. On the other hand, there is growing evidence implicating dysregulated glutamate receptor trafficking in the pathophysiology of several neuropsychiatric disorders. This review provides up-to-date information on the molecular determinants regulating trafficking and surface expression of metabotropic glutamate (mGlu) receptors in the rodent and human brain and discusses the role of mGluR trafficking in maladaptive synaptic plasticity produced by addictive drugs. As substantial evidence links glutamatergic dysfunction to the progression and the severity of drug addiction, advances in our understanding of mGluR trafficking may provide opportunities for the development of novel pharmacotherapies of addiction and other neuropsychiatric disorders.

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