@article{TretterMukherjeeMaricetal.2012,
  author    = {Tretter, Verena and Mukherjee, Jayanta and Maric, Hans-Michael and Schindelin, Hermann and Sieghart, Werner and Moss, Stephen J.},
  title     = {Gephyrin, the enigmatic organizer at GABAergic synapses},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {6},
  journal   = {Frontiers in Cellular Neuroscience},
  number    = {23},
  doi       = {10.3389/fncel.2012.00023},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133356},
  year      = {2012},
  abstract  = {GABA(A) receptors are clustered at synaptic sites to achieve a high density of postsynaptic receptors opposite the input axonal terminals. This allows for an efficient propagation of GABA mediated signals, which mostly result in neuronal inhibition. A key organizer for inhibitory synaptic receptors is the 93 kDa protein gephyrin that forms oligomeric superstructures beneath the synaptic area. Gephyrin has long been known to be directly associated with glycine receptor beta subunits that mediate synaptic inhibition in the spinal cord. Recently, synaptic GABA(A) receptors have also been shown to directly interact with gephyrin and interaction sites have been identified and mapped within the intracellular loops of the GABA(A) receptor alpha 1, alpha 2, and alpha 3 subunits. Gephyrin-binding to GABA(A) receptors seems to be at least one order of magnitude weaker than to glycine receptors (GlyRs) and most probably is regulated by phosphorylation. Gephyrin not only has a structural function at synaptic sites, but also plays a crucial role in synaptic dynamics and is a platform for multiple protein-protein interactions, bringing receptors, cytoskeletal proteins and downstream signaling proteins into close spatial proximity.},
  language  = {en}
}
@article{KasaragodSchindelin2019,
  author    = {Kasaragod, Vikram Babu and Schindelin, Hermann},
  title     = {Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin},
  series = {Frontiers in Molecular Neuroscience},
  volume    = {12},
  journal   = {Frontiers in Molecular Neuroscience},
  issn      = {1662-5099},
  doi       = {10.3389/fnmol.2019.00191},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189308},
  pages     = {191},
  year      = {2019},
  abstract  = {γ-Aminobutyric acid type A receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABAARs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABAARs are key drug targets. The majority of synaptic GABAARs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3-M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABAAR provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABAARs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABAARs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.},
  language  = {en}
}
@article{KasaragodSchindelin2019,
  author    = {Kasaragod, Vikram Babu and Schindelin, Hermann},
  title     = {Structure of heteropentameric GABA\(_A\) receptors and receptor-anchoring properties of gephyrin},
  series = {Frontiers in Molecular Neuroscience},
  volume    = {12},
  journal   = {Frontiers in Molecular Neuroscience},
  number    = {191},
  doi       = {10.3389/fnmol.2019.00191},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201886},
  year      = {2019},
  abstract  = {γ-Aminobutyric acid type A receptors (GABA\(_A\)Rs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABA\(_A\)Rs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABA\(_A\)Rs are key drug targets. The majority of synaptic GABA\(_A\)Rs are anchored at the inhibitory postsynaptic membrane by the principal scaffolding protein gephyrin, which acts as the central organizer in maintaining the architecture of the inhibitory postsynaptic density (iPSD). This interaction is mediated by the long intracellular loop located in between transmembrane helices 3 and 4 (M3-M4 loop) of the receptors and a universal receptor-binding pocket residing in the C-terminal domain of gephyrin. In 2014, the crystal structure of the β3-homopentameric GABA\(_A\)R provided crucial information regarding the architecture of the receptor; however, an understanding of the structure and assembly of heteropentameric receptors at the atomic level was lacking. This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABA\(_A\)Rs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABA\(_A\)Rs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.},
  language  = {en}
}
@article{ImamChoudhuryHeinzeetal.2022,
  author    = {Imam, Nasir and Choudhury, Susobhan and Heinze, Katrin G. and Schindelin, Hermann},
  title     = {Differential modulation of collybistin conformational dynamics by the closely related GTPases Cdc42 and TC10},
  series = {Frontiers in Synaptic Neuroscience},
  volume    = {14},
  journal   = {Frontiers in Synaptic Neuroscience},
  issn      = {1663-3563},
  doi       = {10.3389/fnsyn.2022.959875},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282816},
  year      = {2022},
  abstract  = {Interneuronal synaptic transmission relies on the proper spatial organization of presynaptic neurotransmitter release and its reception on the postsynaptic side by cognate neurotransmitter receptors. Neurotransmitter receptors are incorporated into and arranged within the plasma membrane with the assistance of scaffolding and adaptor proteins. At inhibitory GABAergic postsynapses, collybistin, a neuronal adaptor protein, recruits the scaffolding protein gephyrin and interacts with various neuronal factors including cell adhesion proteins of the neuroligin family, the GABAA receptor α2-subunit and the closely related small GTPases Cdc42 and TC10 (RhoQ). Most collybistin splice variants harbor an N-terminal SH3 domain and exist in an autoinhibited/closed state. Cdc42 and TC10, despite sharing 67.4\% amino acid sequence identity, interact differently with collybistin. Here, we delineate the molecular basis of the collybistin conformational activation induced by TC10 with the aid of recently developed collybistin FRET sensors. Time-resolved fluorescence-based FRET measurements reveal that TC10 binds to closed/inactive collybistin leading to relief of its autoinhibition, contrary to Cdc42, which only interacts with collybistin when forced into an open state by the introduction of mutations destabilizing the closed state of collybistin. Taken together, our data describe a TC10-driven signaling mechanism in which collybistin switches from its autoinhibited closed state to an open/active state.},
  language  = {en}
}