In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 41 ( 2005-10-11), p. 14871-14876
Abstract:
The efficacy of synaptic inhibition depends on the number of γ-aminobutyric acid type A receptors (GABA A Rs) expressed on the cell surface of neurons. The clathrin adaptor protein 2 (AP2) complex is a critical regulator of GABA A R endocytosis and, hence, surface receptor number. Here, we identify a previously uncharacterized atypical AP2 binding motif conserved within the intracellular domains of all GABA A R 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 GABA A R 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 GABA A R current. These effects of pepβ3 on GABA A R current were occluded by inhibitors of dynamin-dependent endocytosis supporting an action of pepβ3 on GABA A R endocytosis. Therefore phospho-dependent regulation of AP2 binding to GABA A Rs provides a mechanism to specify receptor cell surface number and the efficacy of inhibitory synaptic transmission.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0506653102
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2005
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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