@article{KitzenmaierSchaeferKasaragodetal.2019,
  author    = {Kitzenmaier, Alexandra and Schaefer, Natascha and Kasaragod, Vikram Babu and Polster, Tilman and Hantschmann, Ralph and Schindelin, Hermann and Villmann, Carmen},
  title     = {The P429L loss of function mutation of the human glycine transporter 2 associated with hyperekplexia},
  series = {European Journal of Neuroscience},
  volume    = {50},
  journal   = {European Journal of Neuroscience},
  number    = {12},
  doi       = {10.1111/ejn.14533},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206158},
  pages     = {3906-3920},
  year      = {2019},
  abstract  = {Glycine transporter 2 (GlyT2) mutations across the entire sequence have been shown to represent the presynaptic component of the neurological disease hyperekplexia. Dominant, recessive and compound heterozygous mutations have been identified, most of them leading to impaired glycine uptake. Here, we identified a novel loss of function mutation of the GlyT2 resulting from an amino acid exchange of proline 429 to leucine in a family with both parents being heterozygous carriers. A homozygous child suffered from severe neuromotor deficits. We characterised the GlyT2P429L variant at the molecular, cellular and protein level. Functionality was determined by glycine uptake assays. Homology modelling revealed that the mutation localises to α-helix 5, presumably disrupting the integrity of this α-helix. GlyT2P429L shows protein trafficking through various intracellular compartments to the cellular surface. However, the protein expression at the whole cell level was significantly reduced. Although present at the cellular surface, GlyT2P429L demonstrated a loss of protein function. Coexpression of the mutant with the wild-type protein, reflecting the situation in the parents, did not affect transporter function, thus explaining their non-symptomatic phenotype. Nevertheless, when the mutant was expressed in excess compared with the wild-type protein, glycine uptake was significantly reduced. Thus, these data demonstrate that the proline residue at position 429 is structurally important for the correct formation of α-helix 5. The failure in functionality of the mutated GlyT2 is most probably due to structural changes localised in close proximity to the sodium-binding site of the transporter.},
  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}
}