TY  - JOUR
A1  - Scholz, Nicole
A1  - Gehring, Jennifer
A1  - Guan, Chonglin
A1  - Ljaschenko, Dmitrij
A1  - Fischer, Robin
A1  - Lakshmanan, Vetrivel
A1  - Kittel, Robert J.
A1  - Langenhan, Tobias
T1  - The adhesion GPCR Latrophilin/CIRL shapes mechanosensation
JF  - Cell Reports
N2  - G-protein-coupled receptors (GPCRs) are typically regarded as chemosensors that control cellular states in response to soluble extracellular cues. However, the modality of stimuli recognized through adhesion GPCR (aGPCR), the second largest class of the GPCR superfamily, is unresolved. Our study characterizes the Drosophila aGPCR Latrophilin/dCirl, a prototype member of this enigmatic receptor class. We show that dCirl shapes the perception of tactile, proprioceptive, and auditory stimuli through chordotonal neurons, the principal mechanosensors of Drosophila. dCirl sensitizes these neurons for the detection of mechanical stimulation by amplifying their input-output function. Our results indicate that aGPCR may generally process and modulate the perception of mechanical signals, linking these important stimuli to the sensory canon of the GPCR superfamily.
KW  - \(\alpha\)-latrotoxin
KW  - chordotonal organs
KW  - Johnstons organ
KW  - ligand CD55
KW  - hearing
KW  - binding
KW  - shear stress
KW  - protein-coupled receptors
KW  - drosophila larvae
KW  - domain
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148626
VL  - 11
ER  - 
TY  - JOUR
A1  - Atak, Sinem
A1  - Langlhofer, Georg
A1  - Schaefer, Natascha
A1  - Kessler, Denise
A1  - Meiselbach, Heike
A1  - Delto, Carolyn
A1  - Schindelin, Hermann
A1  - Villmann, Carmen
T1  - Disturbances of ligand potency and enhanced degradation of the human glycine receptor at affected positions G160 and T162 originally identified in patients suffering from hyperekplexia
JF  - Frontiers in Molecular Neuroscience
N2  - Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GIyR) undergoes direct interaction with the incoming ligand via a cation-π interaction. Recently, we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GIyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GIyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER toward the ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is delivered to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, 1162 affects primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.
KW  - mutations
KW  - trafficking
KW  - domain
KW  - hyperekplexia
KW  - loop B
KW  - side chain properties
KW  - ligand potencies
KW  - Cys-loop receptor
KW  - glycine receptor
KW  - site
KW  - activation
KW  - binding
KW  - channel
KW  - mechanisms
KW  - dominant
KW  - startle
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144818
VL  - 8
IS  - 79
ER  -