Regulation of inhibitory synaptic transmission by a conserved atypical interaction of GABA(A) receptor beta- and gamma-subunits with the clathrin AP2 adaptor.
The number of surface and synaptic GABA(A) receptors is an important determinant of inhibitory synapse strength. Surface receptor number is in part controlled by removal of receptors from the membrane by interaction with the clathrin adaptor AP2. Here we demonstrate that there are two binding sites for AP2 in the gamma2-subunit: a Yxxvarphi type motif specific to gamma2-subunits and a basic patch AP2 binding motif, that is also found in GABA(A) receptor beta-subunits. Blocking GABA(A) receptor-AP2 interactions using a peptide that inhibits AP2 binding to GABA(A) receptors via the conserved basic patch mechanism increases synaptic responses within minutes, whereas simultaneously blocking both binding mechanisms has an additive effect. These data suggest that multiple AP2 internalization signals control the levels of surface and synaptic GABA(A) receptors to regulate synaptic inhibition.
Smith
Katharine R
KR
Department of Neuroscience, University College London, London WC1E 6BT, UK.
McAinsh
Kristina
K
Chen
Guojun
G
Arancibia-Carcamo
I Lorena
IL
Haucke
Volker
V
Yan
Zhen
Z
Moss
Stephen J
SJ
Kittler
Josef T
JT
D033962:Adaptor Protein Complex 2 / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000502:physiology*; D016415:Sequence Alignment; D050863:Synaptotagmin I / Q000494:pharmacology; D013997:Time Factors
D033962:Adaptor Protein Complex 2; D021122:Protein Subunits; D011963:Receptors, GABA-A; D050863:Synaptotagmin I; C494312:Syt1 protein, rat