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The Journal of Neuroscience, September 10, 2003, 23(23):8330-8339
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Complex Formation between the Postsynaptic Scaffolding Protein Gephyrin, Profilin, and Mena: A Possible Link to the Microfilament System
Torsten Giesemann,1 Günter Schwarz,2 Ralph Nawrotzki,3 Kerstin Berhörster,1 Martin Rothkegel,1 Kathrin Schlüter,1 Nils Schrader,2,4 Hermann Schindelin,4 Ralf R. Mendel,2 Joachim Kirsch,3 andBrigitte M. Jockusch1 1Cell Biology, Zoological Institute, Technical University of Braunschweig, D-38092 Braunschweig, Germany, 2Institute for Plant Science, Technical University of Braunschweig, D-38023 Braunschweig, Germany, 3Department of Anatomy and Cellular Neurobiology, University of Ulm, D-89069 Ulm, Germany, and 4Department of Biochemistry and Center for Structural Biology, State University of New York at Stony Brook, Stony Brook, New York 11794-5115
Gephyrin is an essential component of the postsynaptic cortical protein network of inhibitory synapses. Gephyrin-based scaffolds participate in the assembly as well as the dynamics of receptor clusters by connecting the cytoplasmic domains of glycine and GABAA receptor polypeptides to two cytoskeletal systems, microtubules and microfilaments. Although there is evidence for a physical linkage between gephyrin and microtubules, the interaction between gephyrin and microfilaments is not well understood so far. Here, we show that neuronal gephyrin interacts directly with key regulators of microfilament dynamics, profilin I and neuronal profilin IIa, and with microfilament adaptors of the mammalian enabled (Mena)/vasodilator stimulated phosphoprotein (VASP) family, including neuronal Mena. Profilin and Mena/VASP coprecipitate with gephyrin from tissue and cells, and complex formation requires the E-domain of gephyrin, not the proline-rich central domain. Consequently, gephyrin is not a ligand for the proline-binding motif of profilins, as suspected previously. Instead, it competes with G-actin and phospholipids for the same binding site on profilin. Gephyrin, profilin, and Mena/VASP colocalize at synapses of rat spinal cord and cultivated neurons and in gephyrin clusters expressed in transfected cells. Thus, Mena/VASP and profilin can contribute to the postulated linkage between receptors, gephyrin scaffolds, and the microfilament system and may regulate the microfilament-dependent receptor packing density and dynamics at inhibitory synapses.
Key words: gephyrin; postsynaptic receptor dynamics; Mena; profilins; synaptic efficacy; VASP
Received June 9, 2003; revised July 24, 2003; accepted July 24, 2003.
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