PKC modulation of GABAA receptor endocytosis and function is inhibited by mutation of a dileucine motif within the receptor β2 subunit

Herring, Dina; Huang, Ren-Qi; Singh, Meharvan; Dillon, Glenn H.; Leidenheimer, Nancy J.

doi:10.1016/j.neuropharm.2004.09.015

Cited by 58 publications

(71 citation statements)

References 58 publications

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“…The mechanism by which PKC inhibits group II mGluR function remains unclear. Given that PKC activation has been reported previously to promote endocytosis of several neurotransmitter receptors including AMPA (Chung et al, 2000), somatostatin 2A (Elberg et al, 2002) and GABA A receptors (Herring et al, 2005), it is possible that PKC activation promotes group II mGluR endocytosis and decreases cell surface expression of the receptor. This seems unlikely, however, because the levels of surface mGluR 2 , a major receptor sub- type of group II mGluR to mediate the action of DCG-IV seen in this study, remained unaffected after repeated exposure to cocaine.…”

Section: Discussionmentioning

confidence: 98%

Repeated Cocaine Administration Impairs Group II Metabotropic Glutamate Receptor-Mediated Long-Term Depression in Rat Medial Prefrontal Cortex

et al. 2007

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Section: Discussionmentioning

confidence: 98%

Repeated Cocaine Administration Impairs Group II Metabotropic Glutamate Receptor-Mediated Long-Term Depression in Rat Medial Prefrontal Cortex

et al. 2007

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“…In addition, since this motif overlaps with the 4.1-binding site, phosphorylation at T1292 might disrupt association with the scaffolding molecule. Several channels, transporters and receptors are regulated by PKC for their surface stability and endocytosis (Martin and Henley, 2004;Herring et al, 2005;Holton et al, 2005). However, the mechanisms mediating the conditional trafficking signals are complex and are not completely elucidated.…”

Section: Journal Of Cell Science 122 (18)mentioning

confidence: 99%

“…However, the mechanisms mediating the conditional trafficking signals are complex and are not completely elucidated. PKC-dependent phosphorylation of the GABA and glycine receptors might increase their dileucine-based endocytosis (Herring et al, 2005;Huang et al, 2007). PKC phosphorylation of the AMPA receptor subunit GluR2 at Ser880 stimulates its internalization through the disruption of interactions with the PDZ partners GRIP/ABP (Seidenman et al, 2003).…”

Section: Journal Of Cell Science 122 (18)mentioning

confidence: 99%

Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis

Bel

Oguievetskaia

Pitaval

et al. 2009

Journal of Cell Science

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Contactin-associated protein 2 (Caspr2) is a neuronal membrane protein that is mutated in autism and related disorders. Although it is highly enriched at juxtaparanodes of Ranvier where it is essential for Shaker-type K+ channel clustering, little is known about its function and regulation. In the present study, we examined the polarized expression of Caspr2 in hippocampal neurons using extracellular hemagglutinin (HA)-tagged Caspr2 constructs. We found that Caspr2 was targeted to the axonal surface, but colocalized with early endosomes in the somatodendritic compartment. The inhibition of endocytosis using a Dynamin-1 mutant or treatment with Dynasore prevented Caspr2 internalization from the dendrites and cell body. We identified a short sequence included into the 4.1B-binding domain that is required for the endocytosis of Caspr2. This sequence contains a protein kinase C (PKC) substrate motif on Thr1292, and point mutation of this residue or treatment with a PKC inhibitor prevented the somatodendritic internalization of Caspr2. Thus, the PKC-dependent trafficking of Caspr2 underlies its polarized expression in hippocampal neurons.

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“…It has been reported that GABA Areceptor β and γ subunits associate with AP2, and therefore recombinant GABA A receptors are constitutively endocytosed (36). An AP2 adaptin dileucinebinding motif on the GABA A -receptor β subunits was shown to be critical for the receptor endocytosis, and a peptide corresponding to the dileucine motif prevented PKC-mediated GABA A -receptor endocytosis, and the endocytosis was also prevented by the dynamin K44A mutant (34,37). Recently, an atypical AP2-binding motif conserved within all β subunits of the GABA A receptor, in which a serine residue that can be phosphorylated is present, was reported to associate with the µ2 subunit of AP2 (38).…”

Section: / 409mentioning

confidence: 99%

“…The process of the endocytosis of GABA A receptors involves a clathrinmediated dynamin-dependent mechanism in the recombinant expression system in HEK cells (34,36,37). Clathrin-mediated endocytosis is a major vesicular internalization mechanism in eukaryotic cells.…”

Section: / 409mentioning

confidence: 99%

Regulation of GABAA-Receptor Surface Expression With Special Reference to the Involvement of GABARAP (GABAA Receptor-Associated Protein) and PRIP (Phospholipase C-Related, but Catalytically Inactive Protein)

et al. 2007

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Abstract. GABA A receptors are heteropentameric ligand-gated chloride channels composed of a variety of subunits, including α1 -6, β1 -3, γ1 -3, δ, ε, θ, and π, and play a key role in controlling inhibitory neuronal activity. Modification of the efficacy of the synaptic strength is produced by changes in both the number of neuronal surface receptors and pentameric molecular assembly, leading to differences of sensitivity to neurotransmitters and neuromimetic drugs. Therefore, it is important to understand the molecular mechanisms regulating the so-called "life cycle of GABA A receptors" including sequential pentameric assembly at the site synthesized, intracellular transport through the Golgi apparatus and the cytoplasm, insertion into the cell membrane, functional modulation at the cell surface, and finally internalization, followed by either recycling back to the surface membrane or lysosomal degradation. This review is focused on events related to the surface expression of the receptor containing the γ2 subunit and clathrin / AP2 complex-mediated phospho-regulated endocytosis of the receptor, with special reference to the function of novel GABA A receptor modulators, GABARAP (GABA A receptorassociated protein) and PRIP (phospholipase C-related, but catalytically inactive protein).

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PKC modulation of GABAA receptor endocytosis and function is inhibited by mutation of a dileucine motif within the receptor β2 subunit

Cited by 58 publications

References 58 publications

Repeated Cocaine Administration Impairs Group II Metabotropic Glutamate Receptor-Mediated Long-Term Depression in Rat Medial Prefrontal Cortex

Repeated Cocaine Administration Impairs Group II Metabotropic Glutamate Receptor-Mediated Long-Term Depression in Rat Medial Prefrontal Cortex

Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis

Regulation of GABAA-Receptor Surface Expression With Special Reference to the Involvement of GABARAP (GABAA Receptor-Associated Protein) and PRIP (Phospholipase C-Related, but Catalytically Inactive Protein)

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