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Complex roles of GEFs and gephyrin in inhibitory GABA-A and glycine receptor clustering
Selected GABA-A and glycine receptor subtypes are clustered at inhibitory synapses via interactions with the scaffolding protein gephyrin, which in turn is translocated to inhibitory synapses by collybistin, a guanine nucleotide exchange factor for Cdc42 with neuroligin 2-dependent activity (Poulopoulos et al 2009, Neuron 63: 628-642). Consistent with this hypothesis, we have shown that genetic defects in ARHGEF9, encoding human collybistin, give rise to a range of symptoms consistent with a loss of GABA-AR subtypes, including anxiety, seizures and intellectual disability (Harvey et al 2004, J Neurosci 24: 5816-5826; Kalscheuer et al 2009, Hum Mutat 30:61-68). However, evidence from Arhgef9 knockout mice suggests that collybistin is only required for clustering a subset of GABA-ARs in the hippocampus and the basolateral amygdala (Papadopoulos et al 2007, EMBO J 26: 3888-3899), suggesting that additional GEFs are involved in clustering of other GABA-AR and GlyR subtypes. Future research aims to: i) Characterise two novel GEFs (IQSEC2 and IQSEC3) that may be responsible for clustering GlyRs and other GABA-AR subtypes (Fukaya et al 2010, J Neurochem 116: 1122-1137) and ii) Develop new functional assays for IQSEC2/IQSEC3 variants identified in X-linked or autosomal intellectual disability (Shoubridge et al 2010, Nat Genet 42: 486-488). Key collaborators include: Vera Kalscheuer (MPI for Molecular Genetics, Berlin), Hiroyuki Sakagami (Kitasato University, Japan), Cheryl Shoubridge and Jozef Gecz (Women's and Children's Hospital, Adelaide, Australia), Charles Schwartz (Greenwood Genetic Center, South Carolina, USA), Randall Walikonis (University of Connecticut, USA).
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