TY  - JOUR
A1  - Schaefer, Natscha
A1  - Vogel, Nicolas
A1  - Villmann, Carmen
T1  - Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?
JF  - Frontiers in Molecular Neuroscience
N2  - Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the  (spasmodic, oscillator, cincinnati, Nmf11) or the  (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABA(A) receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.
KW  - GlyRs
KW  - rescue
KW  - hyperekplexia
KW  - knockout mice
KW  - spontaneous mouse mutants
KW  - synaptic inhibition
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123839
VL  - 5
IS  - 98
ER  - 
TY  - JOUR
A1  - Langlhofer, Georg
A1  - Villmann, Carmen
T1  - The Intracellular Loop of the Glycine Receptor: It's not all about the Size
JF  - Frontiers in Molecular Neuroscience
N2  - The family of Cys-loop receptors (CLRs) shares a high degree of homology and sequence identity. The overall structural elements are highly conserved with a large extracellular domain (ECD) harboring an α-helix and 10 β-sheets. Following the ECD, four transmembrane domains (TMD) are connected by intracellular and extracellular loop structures. Except the TM3–4 loop, their length comprises 7–14 residues. The TM3–4 loop forms the largest part of the intracellular domain (ICD) and exhibits the most variable region between all CLRs. The ICD is defined by the TM3–4 loop together with the TM1–2 loop preceding the ion channel pore. During the last decade, crystallization approaches were successful for some members of the CLR family. To allow crystallization, the intracellular loop was in most structures replaced by a short linker present in prokaryotic CLRs. Therefore, no structural information about the large TM3–4 loop of CLRs including the glycine receptors (GlyRs) is available except for some basic stretches close to TM3 and TM4. The intracellular loop has been intensively studied with regard to functional aspects including desensitization, modulation of channel physiology by pharmacological substances, posttranslational modifications, and motifs important for trafficking. Furthermore, the ICD interacts with scaffold proteins enabling inhibitory synapse formation. This review focuses on attempts to define structural and functional elements within the ICD of GlyRs discussed with the background of protein-protein interactions and functional channel formation in the absence of the TM3–4 loop.
KW  - posttranslational modifications
KW  - GlyR receptors
KW  - synaptic inhibition
KW  - intracellular domain
KW  - interaction partners
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165394
IS  - 9
ER  - 
TY  - JOUR
A1  - Kirmse, Knut
T1  - Non-linear GABA\(_{A}\) receptors promote synaptic inhibition in developing neurons
JF  - Pflügers Archiv - European Journal of Physiology
N2  - No abstract available.
KW  - synaptic inhibition
KW  - neurons
KW  - GABA\(_{A}\) receptors
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267674
SN  - 1432-2013
VL  - 474
IS  - 2
ER  -