Collybistin splice variants differentially interact with gephyrin and Cdc42 to regulate gephyrin clustering at GABAergic synapses

Tyagarajan, S.K., Ghosh, H., Harvey, K. and Fritschy, J-M. (2011) Collybistin splice variants differentially interact with gephyrin and Cdc42 to regulate gephyrin clustering at GABAergic synapses. Journal of Cell Science, 124 (16). pp. 2786-2796. 10.1242/jcs.086199.

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DOI: 10.1242/jcs.086199

Abstract

Collybistin (CB) is a guanine-nucleotide-exchange factor (GEF) selectively activating Cdc42. CB mutations cause X-linked mental retardation due to defective clustering of gephyrin, a postsynaptic protein associated with both glycine and GABAA receptors. Using a combination of biochemistry and cell biology we provide novel insights into the roles of the CB2 splice variants, CB2SH3+ and CB2SH3-, and their substrate, Cdc42, in regulating gephyrin clustering at GABAergic synapses. Transfection of Myc-tagged CB2SH3+ and CB2SH3- into cultured neurons revealed strong, but distinct, effects promoting postsynaptic gephyrin clustering, denoting mechanistic differences in their function. In addition, overexpression of constitutively active or dominant-negative Cdc42 mutants identified a new function of Cdc42 in regulating the shape and size of postsynaptic gephyrin clusters. Using biochemical assays and native brain tissue, we identify a direct interaction between gephyrin and Cdc42, independent of its activation state. Finally, our data show that CB2SH3-, but not CB2SH3+, can form a ternary complex with gephyrin and Cdc42, providing a biochemical substrate for the distinct contribution of these CB isoforms in gephyrin clustering at GABAergic postsynaptic sites. Taken together, our results identify CB and Cdc42 as major regulators of GABAergic postsynaptic densities

Item Type:Article
Uncontrolled Keywords:Cdc42; Collybistin; GABAaR; Gephyrin; RhoGEF
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:2776
Journal or Publication Title:Journal of Cell Science
Deposited By:Library Staff
Deposited On:10 Feb 2012 09:13
Last Modified:10 Feb 2012 09:13

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