Kittler, J.T., Chen, G.C., Honing, S., Bogdanov, Y., McAinsh, K., Arancibia-Carcamo , L., Jovanovic, J.N., Pangalos, M.N., Haucke, V., Yan, Z. and Moss, S.J. (2005) Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission. Proceedings of the National Academy of Sciences, 102 (41). pp. 14871-14876. 10.1073/pnas.0506653102 .
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The efficacy of synaptic inhibition depends on the number of γ-aminobutyric acid type A receptors (GABAARs) expressed on the cell surface of neurons. The clathrin adaptor protein 2 (AP2) complex is a critical regulator of GABAAR endocytosis and, hence, surface receptor number. Here, we identify a previously uncharacterized atypical AP2 binding motif conserved within the intracellular domains of all GABAAR β subunit isoforms. This AP2 binding motif (KTHLRRRSSQLK in the β3 subunit) incorporates the major sites of serine phosphorylation within receptor β subunits, and phosphorylation within this site inhibits AP2 binding. Furthermore, by using surface plasmon resonance, we establish that a peptide (pepβ3) corresponding to the AP2 binding motif in the GABAAR β3 subunit binds to AP2 with high affinity only when dephosphorylated. Moreover, the pepβ3 peptide, but not its phosphorylated equivalent (pepβ3-phos), enhanced the amplitude of miniature inhibitory synaptic current and whole cell GABAAR current. These effects of pepβ3 on GABAAR current were occluded by inhibitors of dynamin-dependent endocytosis supporting an action of pepβ3 on GABAAR endocytosis. Therefore phospho-dependent regulation of AP2 binding to GABAARs provides a mechanism to specify receptor cell surface number and the efficacy of inhibitory synaptic transmission.
|Departments, units and centres:||Department of Pharmacology > Department of Pharmacology|
|Journal or Publication Title:||Proceedings of the National Academy of Sciences|
|Deposited By:||Library Staff|
|Deposited On:||01 Apr 2011 16:56|
|Last Modified:||08 Apr 2011 14:32|
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