title: Collybistin activation by GTP-TC10 enhances postsynaptic gephyrin clustering and hippocampal GABAergic neurotransmission.
abstract: In many brain regions, gephyrin and GABAA receptor clustering at developing inhibitory synapses depends on the guanine nucleotide exchange factor collybistin (Cb). The vast majority of Cb splice variants contain an autoinhibitory src homology 3 domain, and several synaptic proteins are known to bind to this SH3 domain and to thereby activate gephyrin clustering. However, many functional GABAergic synapses form independently of the known Cb-activating proteins, indicating that additional Cb activators must exist. Here we show that the small Rho-like GTPase TC10 stimulates Cb-dependent gephyrin clustering by binding in its active, GTP-bound state to the pleckstrin homology domain of Cb. Overexpression of a constitutively active TC10 variant in neurons causes an increase in the density of synaptic gephyrin clusters and mean miniature inhibitory postsynaptic current amplitudes, whereas a dominant negative TC10 variant has opposite effects. The enhancement of Cb-induced gephyrin clustering by GTP-TC10 does not depend on the guanine nucleotide exchange activity of Cb but involves an interaction that resembles reported interactions of other small GTPases with their effectors. Our data indicate that GTP-TC10 activates the major src homology 3 domain-containing Cb variants by relieving autoinhibition and thus define an alternative GTPase-driven signaling pathway in the genesis of inhibitory synapses.
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Mayer
authors.forename: Rohit
authors.initials: R
authors.lastname: Kumar
authors.forename: Mamta
authors.initials: M
authors.lastname: Jaiswal
authors.forename: Tolga
authors.initials: T
authors.lastname: Soykan
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Heinrich
authors.initials: H
authors.lastname: Betz
authors.forename: Jeong-Seop
authors.initials: JS
authors.lastname: Rhee
authors.forename: Theofilos
authors.initials: T
authors.lastname: Papadopoulos
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D055366:Synaptic Potentials / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C577410:ARHGEF9 protein, human; C577404:Arhgef9 protein, rat; D002352:Carrier Proteins; D008565:Membrane Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C073441:gephyrin; D006160:Guanosine Triphosphate; C503256:RHOQ protein, human; C503262:Rhoq protein, rat; D020741:rho GTP-Binding Proteins
keywords: Cdc42; RhoQ; neuroligin; postsynaptic scaffold; synaptogenesis