TY - JOUR
T1 - Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission
AU - Maric, Hans Michael
AU - Hausrat, Torben Johann
AU - Neubert, Franziska
AU - Dalby, Nils Ole
AU - Doose, Sören
AU - Sauer, Markus
AU - Kneussel, Matthias
AU - Strømgaard, Kristian
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 3-Aminobutyric acid type A and glycine receptors are the major mediators of fast synaptic inhibition in the human central nervous system and are established drug targets. However, all drugs targeting these receptors bind to the extracellular ligand-binding domain of the receptors, which inherently is associated with perturbation of the basic physiological action. Here we pursue a fundamentally different approach, by instead targeting the intracellular receptor-gephyrin interaction. First, we defined the gephyrin peptide-binding consensus sequence, which facilitated the development of gephyrin super-binding peptides and later effective affinity probes for the isolation of native gephyrin. Next, we demonstrated that fluorescent super-binding peptides could be used to directly visualize inhibitory postsynaptic sites for the first time in conventional and super-resolution microscopy. Finally, we demonstrate that the gephyrin super-binding peptides act as acute intracellular modulators of fast synaptic inhibition by modulating receptor clustering, thus being conceptually novel modulators of inhibitory neurotransmission.
AB - 3-Aminobutyric acid type A and glycine receptors are the major mediators of fast synaptic inhibition in the human central nervous system and are established drug targets. However, all drugs targeting these receptors bind to the extracellular ligand-binding domain of the receptors, which inherently is associated with perturbation of the basic physiological action. Here we pursue a fundamentally different approach, by instead targeting the intracellular receptor-gephyrin interaction. First, we defined the gephyrin peptide-binding consensus sequence, which facilitated the development of gephyrin super-binding peptides and later effective affinity probes for the isolation of native gephyrin. Next, we demonstrated that fluorescent super-binding peptides could be used to directly visualize inhibitory postsynaptic sites for the first time in conventional and super-resolution microscopy. Finally, we demonstrate that the gephyrin super-binding peptides act as acute intracellular modulators of fast synaptic inhibition by modulating receptor clustering, thus being conceptually novel modulators of inhibitory neurotransmission.
U2 - 10.1038/nchembio.2246
DO - 10.1038/nchembio.2246
M3 - Journal article
C2 - 27893705
SN - 1552-4450
VL - 13
SP - 153
EP - 160
JO - Nature Chemical Biology
JF - Nature Chemical Biology
M1 - 2246
ER -