title: GIT1 and βPIX are essential for GABA(A) receptor synaptic stability and inhibitory neurotransmission.
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.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Smith
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Davenport
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Manavendra
authors.initials: M
authors.lastname: Pathania
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Vaccaro
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: j.kittler@ucl.ac.uk.
authors.forename: Josef T
authors.initials: JT
authors.lastname: Kittler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D014162:Transfection
chemical_list: C576606:ARHGEF7 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C485647:GIT1 protein, human; D011963:Receptors, GABA-A; D064067:Rho Guanine Nucleotide Exchange Factors