PuSH - Publication Server of Helmholtz Zentrum München: PH-domain-driven targeting of collybistin but not Cdc42 activation is required for synaptic gephyrin clustering.

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Reddy-Alla, S.* ; Schmitt, B.* ; Birkenfeld, J.* ; Eulenburg, V.* ; Dutertre, S.* ; Böhringer, C.R. ; Götz, M. ; Betz, H.* ; Papadopoulos, T.*

PH-domain-driven targeting of collybistin but not Cdc42 activation is required for synaptic gephyrin clustering.

Eur. J. Neurosci. 31, 1173-1184 (2010)

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Open Access Green as soon as Postprint is submitted to ZB.

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Collybistin (Cb) is a brain-specific guanine nucleotide exchange factor (GEF) that is essential for the synaptic clustering of gephyrin and GABAA receptors in selected regions of the mammalian central nervous system. It has been previously proposed that Cb regulates gephyrin clustering by activating Cdc42, and thus acts as a signal transducer in a membrane activation process which labels postsynaptic membrane domains for inhibitory synapse formation. Here, we dissected the functional roles of the Dbl-homology (DH) and pleckstrin homology (PH) domains of the constitutively active splice variant Cb II by substituting conserved amino acid residues that are required for GEF activity towards Cdc42 and phosphoinositide binding, respectively. A Cb II mutant lacking any detectable GEF activity towards Cdc42 was still fully active in inducing gephyrin scaffold formation, both in transfected NIH-3T3 cells and in cultured hippocampal neurons. Furthermore, mice with a forebrain-specific inactivation of the Cdc42 gene displayed normal densities of gephyrin and GABA(A) receptor clusters in the hippocampus. In contrast, substitution of Cb II PH-domain residues essential for phosphoinositide binding abolished gephyrin recruitment to synaptic sites. Our results provide evidence that the formation of gephyrin scaffolds at inhibitory synapses requires an intact Cb II PH-domain but is Cdc42-independent.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cdc42; Collybistin; GABA(A) receptor clustering; Gephyrin; Inhibitory synapse; Mouse

ISSN (print) / ISBN 0953-816X

e-ISSN 1460-9568

Journal European Journal of Neuroscience

Quellenangaben Volume: 31, Issue: 7, Pages: 1173-1184

Publisher Wiley

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Stem Cell Research (ISF)