ArticleThe Journal of biological chemistry2013
Endoplasmic reticulum-associated degradation controls cell surface expression of γ-aminobutyric acid, type B receptors.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant.Brain : a journal of neurology · 2025Article
- The E3 ubiquitin ligase MARCH1 mediates downregulation of plasma membrane GABAScientific reports · 2025Article
- Circadian Oscillation Pattern of Endoplasmic Reticulum Quality Control (ERQC) Components in Human Embryonic Kidney HEK293 Cells.Journal of circadian rhythms · 2023Article
- Mechanisms and Regulation of Neuronal GABACurrent topics in behavioral neurosciences · 2022Review
- Modulation of GABAFrontiers in molecular neuroscience · 2022Article
- Historical perspective and progress on protein ubiquitination at glutamatergic synapses.Neuropharmacology · 2021Review
- CaMolecular neurobiology · 2019Article
- Ubc7/Ube2g2 ortholog in Entamoeba histolytica: connection with the plasma membrane and phagocytosis.Parasitology research · 2018Article
- Diversity of structure and function of GABAProceedings of the Japan Academy. Series B, Physical and biological sciences · 2018Review
- ER-associated degradation regulates Alzheimer's amyloid pathology and memory function by modulating γ-secretase activity.Nature communications · 2017Article
- Evidence for a complex formation between CYP2J5 and mEH in living cells by FRET analysis of membrane protein interaction in the endoplasmic reticulum (FAMPIR).Archives of toxicology · 2017Article
- Membrane Protein Quantity Control at the Endoplasmic Reticulum.The Journal of membrane biology · 2017Review
- Recent insights on principles of synaptic protein degradation.F1000Research · 2017Review
- Lys-63-linked Ubiquitination of γ-Aminobutyric Acid (GABA), Type B1, at Multiple Sites by the E3 Ligase Mind Bomb-2 Targets GABAB Receptors to Lysosomal Degradation.The Journal of biological chemistry · 2016Article
- Molecular Pharmacology of δ-Opioid Receptors.Pharmacological reviews · 2016Review
- Post-endocytotic Deubiquitination and Degradation of the Metabotropic γ-Aminobutyric Acid Receptor by the Ubiquitin-specific Protease 14.The Journal of biological chemistry · 2016Article
- Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.PloS one · 2015Article
- Icariin induces synoviolin expression through NFE2L1 to protect neurons from ER stress-induced apoptosis.PloS one · 2015Article
- Proteasomal degradation of γ-aminobutyric acidB receptors is mediated by the interaction of the GABAB2 C terminus with the proteasomal ATPase Rtp6 and regulated by neuronal activity.The Journal of biological chemistry · 2014Article
- Ubiquitin-proteasome dependent degradation of GABAAα1 in autism spectrum disorder.Molecular autism · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metabotropic GABAB receptors are crucial for controlling the excitability of neurons by mediating slow inhibition in the CNS. The strength of receptor signaling depends on the number of cell surface receptors, which is thought to be regulated by trafficking and degradation mechanisms. Although the mechanisms of GABAB receptor trafficking are studied to some extent, it is currently unclear whether receptor degradation actively controls the number of GABAB receptors available for signaling. Here we tested the hypothesis that proteasomal degradation contributes to the regulation of GABAB receptor expression levels. Blocking proteasomal activity in cultured cortical neurons considerably enhanced total and cell surface expression of GABAB receptors, indicating the constitutive degradation of the receptors by proteasomes. Proteasomal degradation required Lys(48)-linked polyubiquitination of lysines 767/771 in the C-terminal domain of the GABAB2 subunit. Inactivation of these ubiquitination sites increased receptor levels and GABAB receptor signaling in neurons. Proteasomal degradation was mediated by endoplasmic reticulum-associated degradation (ERAD) as shown by the accumulation of receptors in the endoplasmic reticulum upon inhibition of proteasomes, by the increase of receptor levels, as well as receptor signaling upon blocking ERAD function, and by the interaction of GABAB receptors with the essential ERAD components Hrd1 and p97. In conclusion, the data support a model in which the fraction of GABAB receptors available for plasma membrane trafficking is regulated by degradation via the ERAD machinery. Thus, modulation of ERAD activity by changes in physiological conditions may represent a mechanism to adjust receptor numbers and thereby signaling strength.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.