dc.contributor.author
Smith, Katharine R.
dc.contributor.author
Muri, J.
dc.contributor.author
Rao, Y.
dc.contributor.author
Browaski, M.
dc.contributor.author
Gruenig, M. C.
dc.contributor.author
Sheehan, D. F.
dc.contributor.author
Haucke, Volker
dc.contributor.author
Kittler, J. T.
dc.date.accessioned
2018-06-08T03:30:02Z
dc.date.available
2014-08-13
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/15303
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-19491
dc.description.abstract
The strength of synaptic inhibition can be controlled by the stability and
endocytosis of surface and synaptic GABAA receptors (GABAARs), but the surface
receptor dynamics that underpin GABAAR recruitment to dendritic endocytic
zones (EZs) have not been investigated. Stabilization of GABAARs at EZs is
likely to be regulated by receptor interactions with the clathrin-adaptor AP2,
but the molecular determinants of these associations remain poorly understood.
Moreover, although surface GABAAR downmodulation plays a key role in
pathological disinhibition in conditions such as ischemia and epilepsy,
whether this occurs in an AP2-dependent manner also remains unclear. Here we
report the characterization of a novel motif containing three arginine
residues (405RRR407) within the GABAAR β3-subunit intracellular domain (ICD),
responsible for the interaction with AP2 and GABAAR internalization. When this
motif is disrupted, binding to AP2 is abolished in vitro and in rat brain.
Using single-particle tracking, we reveal that surface β3-subunit-containing
GABAARs exhibit highly confined behavior at EZs, which is dependent on AP2
interactions via this motif. Reduced stabilization of mutant GABAARs at EZs
correlates with their reduced endocytosis and increased steady-state levels at
synapses. By imaging wild-type or mutant super-ecliptic pHluorin-tagged
GABAARs in neurons, we also show that, under conditions of oxygen–glucose
deprivation to mimic cerebral ischemia, GABAARs are depleted from synapses in
dendrites, depending on the 405RRR407 motif. Thus, AP2 binding to an RRR motif
in the GABAAR β3-subunit ICD regulates GABAAR residency time at EZs, steady-
state synaptic receptor levels, and pathological loss of GABAARs from synapses
during simulated ischemia.
de
dc.rights.uri
http://creativecommons.org/licenses/by-nc-sa/3.0
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie
dc.title
Stabilization of GABAA Receptors at Endocytic Zones Is Mediated by an AP2
Binding Motif within the GABAA Receptor β3 Subunit
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
Journal of Neuroscience. - 32 (2012), 7, S. 2485-2498
dc.identifier.sepid
27728
dcterms.bibliographicCitation.doi
10.1523/JNEUROSCI.1622-11.2011
dcterms.bibliographicCitation.url
https://doi.org/10.1523/JNEUROSCI.1622-11.2011
refubium.affiliation
Biologie, Chemie, Pharmazie
de
refubium.mycore.fudocsId
FUDOCS_document_000000020699
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000003780
dcterms.accessRights.openaire
open access
dcterms.isPartOf.issn
0270-6474