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Article
Subject Categories: Signal Transduction
The EMBO Journal (2007) 26, 1761–1771, doi:10.1038/sj.emboj.7601625
Published online 8 March 2007
Post-phosphorylation prolyl isomerisation of gephyrin represents a mechanism to modulate glycine receptors function
M Moretto Zita1, Ivan Marchionni1, Elisa Bottos1, Massimo Righi1, Giannino Del Sal2, 3, Enrico Cherubini1 and Paola Zacchi1
1 International School for Advanced Studies, Neuroscience Programme, Area Science Park, Trieste, Italy
2 Laboratorio Nazionale CIB, AREA Science Park, Trieste, Italy
3 Dipartimento di Biochimica Biofisica Chimica delle Macromolecole, Trieste, Italy

To whom correspondence should be addressed
Paola Zacchi, International School for Advanced Studies, Neuroscience Programme, Area Science Park, Basovizza SS14 Km 163.5, 34012 Trieste, Italy. Tel.: +39 403756510; Fax:+39 403756502; E-mail: zacchi@sissa.it

Received 4 August 2006; Accepted 31 January 2007; Published online 8 March 2007.
Abstract
The microtubule binding protein gephyrin plays a prominent role in establishing and maintaining a high concentration of inhibitory glycine receptors juxtaposed to presynaptic releasing sites. Here, we show that endogenous gephyrin undergoes proline-directed phosphorylation, which is followed by the recruitment of the peptidyl-prolyl isomerase Pin1. The interaction between gephyrin and Pin1 is strictly dependent on gephyrin phosphorylation and requires serine–proline consensus sites encompassing the gephyrin proline-rich domain. Upon binding, Pin1 triggers conformational changes in the gephyrin molecule, thus enhancing its ability to bind the beta subunit of GlyRs. Consistently, a downregulation of GlyR clusters was detected in hippocampal neurons derived from Pin1 knockout mice, which was paralleled by a reduction in the amplitude of glycine-evoked currents. Our results suggest that phosphorylation-dependent prolyl isomerisation of gephyrin represents a mechanism for regulating GlyRs function.
Keywords: gephyrin, glycine inhibitory receptors, Pin1, proline directed phosphorylation
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