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GIT1 and βPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission.

Smith, KR; Davenport, EC; Wei, J; Li, X; Pathania, M; Vaccaro, V; Yan, Z; (2014) GIT1 and βPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission. Cell Rep , 9 (1) 298 - 310. 10.1016/j.celrep.2014.08.061. Green open access

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Abstract

Effective inhibitory synaptic transmission requires efficient stabilization of GABA(A) receptors (GABA(A)Rs) at synapses, which is essential for maintaining the correct excitatory-inhibitory balance in the brain. However, the signaling mechanisms that locally regulate synaptic GABA(A)R membrane dynamics remain poorly understood. Using a combination of molecular, imaging, and electrophysiological approaches, we delineate a GIT1/βPIX/Rac1/PAK signaling pathway that modulates F-actin and is important for maintaining surface GABA(A)R levels, inhibitory synapse integrity, and synapse strength. We show that GIT1 and βPIX are required for synaptic GABA(A)R surface stability through the activity of the GTPase Rac1 and downstream effector PAK. Manipulating this pathway using RNAi, dominant-negative and pharmacological approaches leads to a disruption of GABA(A)R clustering and decrease in the strength of synaptic inhibition. Thus, the GIT1/βPIX/Rac1/PAK pathway plays a crucial role in regulating GABA(A)R synaptic stability and hence inhibitory synaptic transmission with important implications for inhibitory plasticity and information processing in the brain.

Type: Article
Title: GIT1 and βPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2014.08.061
Publisher version: http://dx.doi.org/10.1016/j.celrep.2014.08.061
Language: English
Additional information: Copyright © 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1451225
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