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Cited by 49Receptor Mechanisms and SignalingNeuroscience and Neuropharmacology ResearchCellular transport and secretion

Functional modulation of GABAB receptors by protein kinases and receptor trafficking

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Terunuma, Miho, Pangalos, Menelas N., Moss, Stephen J.·2010·Advances in Pharmacology
DOI 10.1016/s1054-3589(10)58005-0PMC PMC2956990
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Abstract

GABA(B) receptors (GABA(B)R) are heterodimeric G protein-coupled receptors (GPCRs) that mediate slow and prolonged inhibitory signals in the central nervous system. The signaling of GPCRs is under stringent control and is subject to regulation by multiple posttranslational mechanisms. The beta-adrenergic receptor is a prototypic GPCR. Like most GPCRs, prolonged exposure of this receptor to agonist induces phosphorylation of multiple intracellular residues that is largely dependent upon the activity of G protein-coupled receptor kinases (GRKs). Phosphorylation terminates receptor-effector coupling and promotes both interaction with beta-arrestins and removal from the plasma membrane via clathrin-dependent endocytosis. Emerging evidence for GABA(B)Rs suggests that these GPCRs do not conform to this mode of regulation. Studies using both native and recombinant receptor preparations have demonstrated that GABA(B)Rs do not undergo agonist-induced internalization and are not GRK substrates. Moreover, whilst GABA(B)Rs undergo clathrin-dependent constitutive endocytosis, it is generally accepted that their rates of internalization are not modified by prolonged agonist exposure. Biochemical studies have revealed that GABA(B)Rs are phosphorylated on multiple residues within the cytoplasmic domains of both the R1 and R2 subunits by cAMP-dependent protein kinase and 5'AMP-dependent protein kinase (AMPK). Here we discuss the role that this phosphorylation plays in determining GABA(B)R effector coupling and their trafficking within the endocytic pathway and go on to evaluate the significance of GABA(B)R phosphorylation in controlling neuronal excitability under normal and pathological conditions.

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  • GABA receptors are regulated by clathrin-dependent endocytosis.

    “Beyond the loss of the GABAergic interneurons, GABA receptors are regulated by clathrin-dependent endocytosis [92,93].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [93]

    Section 4 states that GABAB receptors undergo constitutive clathrin-dependent endocytosis. The cited paper addresses GABAB receptors specifically, so it does not establish the claim for GABA receptors generally. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Cites

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Cited by

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Authors
Terunuma, M., Pangalos, M. N., & Moss, S. J.
Affiliations
  • Tufts University (US)
  • AstraZeneca (United Kingdom) (GB)
ORCID
Venue
Advances in Pharmacology
Publisher
Elsevier
Published
2010
Volume
58
Pages
113-122
ISSN
1054-3589 (ISSN-L)
DOI
10.1016/s1054-3589(10)58005-0
PMC
PMC2956990
OpenAlex
W1764789047
Cited by
49
References
2
Citations by year
2026: 1 · 2025: 1 · 2023: 2 · 2022: 6 · 2020: 6 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 8 · 2014: 5 · 2013: 1 · 2012: 4
FWCI
2.31
Type
book chapter
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Advances in pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association
  • National Institute of Neurological Disorders and Stroke (NS-047478, R01NS051195, P01NS054900, R01NS048045, NS 056359, NS 051195, R01NS056359, R21NS080064, R01NS081986, R03NS065725, R01NS047478, NS054900, NS065725, NS-048045)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
GABAB receptors, G protein-coupled receptors, receptor phosphorylation, protein kinase A, AMPK, receptor internalization, clathrin-mediated endocytosis, receptor trafficking, receptor-effector coupling, neuronal excitability, post-translational regulation
MeSH terms
Animals, Disease, Endocytosis, Humans, Phosphorylation, Protein Kinases, Receptors, GABA-B, Protein Transport

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