Abstract
Gephyrin is a central scaffold protein that mediates development, function, and plasticity of mammalian inhibitory synapses by interacting with various inhibitory synaptic proteins. Here, we show that IQSEC3, a guanine nucleotide exchange factor for ARF6, directly interacts with gephyrin, an interaction that is critical for the inhibitory synapse localization of IQSEC3. Overexpression of IQSEC3 increases inhibitory, but not excitatory, synapse density in a guanine nucleotide exchange factor activity-dependent manner. Conversely, knockdown of IQSEC3 decreases size of gephyrin cluster without altering gephyrin puncta density. Collectively, these data reveal that IQSEC3 acts together with gephyrin to regulate inhibitory synapse development.
Highlights
Postsynaptic scaffolding proteins organize functional synapses and promote reliable synaptic transmission by ensuring the accurate accumulation of postsynaptic receptors in precise apposition to presynaptic release sites
Nine encoded a partial cDNA for IQSEC2/BRAG1, and three encoded a cDNA fragment for IQSEC3/BRAG3 covering an N-terminal region between a CC1 domain and an IQ motif (Fig. 1B)
We found that IQSEC3 immunoprecipitated from crude synaptosome lysates of adult rat brains with IQSEC3 antibodies (JK079; see below) co-immunoprecipitated significant amounts of gephyrin as well as NL-2 and S-SCAM, but not NL-1 or collybistin (Fig. 2B)
Summary
We show that IQSEC3, a guanine nucleotide exchange factor for ARF6, directly interacts with gephyrin, an interaction that is critical for the inhibitory synapse localization of IQSEC3. Postsynaptic scaffolding proteins organize functional synapses and promote reliable synaptic transmission by ensuring the accurate accumulation of postsynaptic receptors in precise apposition to presynaptic release sites. They provide platforms for postsynaptic receptors and regulate downstream signaling cascades to adjust the molecular composition of the postsynaptic machineries that enable postsynaptic plasticity [1, 2]. We show that IQSEC3 directly binds to gephyrin to promote inhibitory synapse formation in an Arf-GEF activitydependent manner in cultured hippocampal neurons. Our results suggest a novel molecular mechanism of inhibitory synapse formation that may link ARF activity to the IQSEC3-gephyrin complex and further imply that IQSEC3 is critical for mediating neuronal inhibition, possibly hinting at its crucial roles in organizing inhibitory neural circuit properties
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