GABAA receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1

Bedford, Fiona K.; Kittler, Josef T.; Muller, Émilie; Thomas, Philip; Uren, Julia M.; Merlo, Daniela; Wisden, William; Triller, Antoine; Smart, Trevor G.; Moss, Stephen J.

doi:10.1038/nn0901-908

Cited by 214 publications

(212 citation statements)

References 43 publications

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“…For example, gephyrin and dystrophin have been shown to play a role in the anchoring of GABA A receptors, although no physical interaction with gephyrin has been demonstrated in vitro (39,40). GABARAP, a microtubuleassociated protein, and Plic-1, an ubiquitin-related protein, interact with GABA A receptor subunits and are involved in receptor trafficking (41,42). MAP1B is a large protein that binds actin and tubulin and is the only GABA C receptor binding partner identified so far.…”

Section: Discussionmentioning

confidence: 99%

Cross-talk and Co-trafficking between ρ1/GABA Receptors and ATP-gated Channels

Boué‐Grabot

Émerit

Toulmé

et al. 2004

Journal of Biological Chemistry

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␥-Aminobutyric-acid (GABA) and ATP ionotropic receptors represent two structurally and functionally different classes of neurotransmitter-gated channels involved in fast synaptic transmission. We demonstrate here that, when the inhibitory 1/GABA and the excitatory P2X 2 receptor channels are co-expressed in Xenopus oocytes, activation of one channel reduces the currents mediated by the other one. This reciprocal inhibitory cross-talk is a receptor-mediated phenomenon independent of agonist cross-modulation, membrane potential, direction of ionic flux, or channel densities. Functional interaction is disrupted when the cytoplasmic C-terminal domain of P2X 2 is deleted or in competition experiments with minigenes coding for the Cterminal domain of P2X 2 or the main intracellular loop of 1 subunits. We also show a physical interaction between P2X 2 and 1 receptors expressed in oocytes and the co-clustering of these receptors in transfected hippocampal neurons. Co-expression with P2X 2 induces retargeting and recruitment of mainly intracellular 1/ GABA receptors to surface clusters. Therefore, molecular and functional cross-talk between inhibitory and excitatory ligand-gated channels may regulate synaptic strength both by activity-dependent current occlusion and synaptic receptors co-trafficking.Neuronal activity is regulated by a number of transmitters acting on different receptor types (1). Fast neurotransmission is achieved through different classes of transmitter-gated channels, including the P2X and nicotinic receptor superfamilies (1, 2). The family of P2X ATP-gated cation channels is composed of seven genes coding for subunits with two transmembrane domains, intracellular N and C termini, and a large extracellular loop (2). The nicotinic superfamily includes the GABA-gated 1 channels along with the acetylcholine, 5-HT 3 , and glycine receptors that share several structural features, including a large extracellular N-terminal domain, four hydrophobic transmembrane domains (M1-M4), and a long cytoplasmic loop connecting M3 and M4 (1). GABA receptor channels have been classified into two subtypes based on their pharmacological properties. GABA A receptors are inhibited by bicuculline, whereas GABA C receptors are insensitive to this antagonist (1). Diversity of GABA A receptors is achieved by pentameric assembly of multiple subunits, including ␣1-6, ␤1-3, ␥1-3, ␦, , and ⑀. GABA C receptors are composed of 1-3 subunits that can assemble into homo-oligomers (3, 4). Recent data suggest that a 1 subunit could co-assemble with a GABA A subunit (5, 6). Neuronal ATP and GABA C ionotropic receptors are involved in fast excitatory and inhibitory synaptic transmission, respectively, and display overlapping distribution in many regions of the nervous system, including DRG, dorsal horn of the spinal cord (7, 8), retina (9 -13), hippocampus (14 -15), cerebellum (14, 16), and anterior pituitary (17, 18).Recently, Jo and co-workers described ATP and GABA corelease from the same axon terminals into the dorsal horn of the spinal ...

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Section: Discussionmentioning

confidence: 99%

Cross-talk and Co-trafficking between ρ1/GABA Receptors and ATP-gated Channels

Boué‐Grabot

Émerit

Toulmé

et al. 2004

Journal of Biological Chemistry

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“…Using the intracellular domain of the GABA A R ␤1 subunit (amino acids 303-425) we screened a rat hippocampal library in pPC86 as described (15,16).…”

Section: Methodsmentioning

confidence: 99%

“…To identify proteins that regulate the endocytic sorting of GABA A Rs, we carried out a Y2H screen of a rat hippocampal library (15,16), with a bait encoding the intracellular domain of the GABA A R ␤1 subunit, and identified several interacting clones that encoded the central domain of rat HAP1 (residues 220-520). This protein exists as two C-terminal splice variants, HAP1a and HAP1b, with molecular masses of 75 and 85 kDa, respectively.…”

Section: Gabaar Endocytosis and Recycling In Neuronsmentioning

confidence: 99%

Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating γ-aminobutyric acid type A receptor membrane trafficking

Kittler

Thomas

Tretter

et al. 2004

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

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204

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␥-Aminobutyric acid type A receptors (GABAARs) are the major sites of fast synaptic inhibition in the brain. An essential determinant for the efficacy of synaptic inhibition is the regulation of GABA A R cell surface stability. Here, we have examined the regulation of GABA AR endocytic sorting, a critical regulator of cell surface receptor number. In neurons, rapid constitutive endocytosis of GABA ARs was evident. Internalized receptors were then either rapidly recycled back to the cell surface, or on a slower time scale, targeted for lysosomal degradation. This sorting decision was regulated by a direct interaction of GABA ARs with Huntingtinassociated protein 1 (HAP1). HAP1 modulated synaptic GABA AR number by inhibiting receptor degradation and facilitating receptor recycling. Together these observations have identified a role for HAP1 in regulating GABA AR sorting, suggesting an important role for this protein in the construction and maintenance of inhibitory synapses.

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“…A glycine receptor has been shown to be internalized upon ubiquitination (Buttner et al 2001). A protein associated with GABA A receptors, Plic-1, indirectly controls the removal of GABA A through endocytosis (Bedford et al 2001). It was found that proteasome inhibitors prevent degradation of internalized GABA A receptors.…”

Section: Postsynaptic Roles Of the Uppmentioning

confidence: 99%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

129

123

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Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

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GABAA receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1

Cited by 214 publications

References 43 publications

Cross-talk and Co-trafficking between ρ1/GABA Receptors and ATP-gated Channels

Cross-talk and Co-trafficking between ρ1/GABA Receptors and ATP-gated Channels

Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating γ-aminobutyric acid type A receptor membrane trafficking

The ubiquitin-proteasome pathway and synaptic plasticity

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