(S)-2-Mercaptohistidine:A First Selective Orthosteric GluK3 Antagonist

International audienceThe development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of (S)-2-hydroxyhistidine (2a) and (S)-2-mercaptohistidine (2b) as mediators of glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, 2b displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range (Ki = 6.42 ± 0.74 μM). The iGluR subtype selectivity ratio for 2b was calculated at ∼30-fold for GluK1/GluK3, GluA3/GluK3, and GluA4/GluK3 and >100-fold for GluK2/GluK3, GluA1/GluK3, and GluA2/GluK3. Unexpectedly, functional characterization of 2b revealed that the compound is an antagonist (Kb = 7.6 μM) at homomeric GluK3 receptors while exhibiting only weak agonist activity at GluA2 (EC50 = 3.25 ± 0.55 mM). The functional properties of 2b were explored further in electrophysiological recordings of mouse hippocampal neurons

Vangl2 in the Dentate Network Modulates Pattern Separation and Pattern Completion

International audienceThe organization of spatial information, including pattern completion and pattern separation processes, relies on the hippocampal circuits, yet the molecular and cellular mechanisms underlying these two processes are elusive. Here, we find that loss of Vangl2, a core PCP gene, results in opposite effects on pattern completion and pattern separation processes. Mechanistically, we show that Vangl2loss maintains young postmitotic granule cells in an immature state, providing increased cellular input for pattern separation. The genetic ablation of Vangl2disrupts granule cell morpho-functional maturation and further prevents CaMKII and GluA1 phosphorylation, disrupting the stabilization of AMPA receptors. As a functional consequence, LTP at lateral perforant path-GC synapses is impaired, leading to defects in pattern completion behavior. In conclusion, we show that Vangl2 exerts a bimodal regulation on young and mature GCs, and its disruption leads to an imbalance in hippocampus-dependent pattern completion and separation processes

p120 Catenin Recruits Cadherins to γ-Secretase and Inhibits Production of Aβ Peptide*S⃞

The γ-secretase complex cleaves many transmembrane proteins, including amyloid precursor protein, EphB and ErbB tyrosine kinase receptors, Notch1 receptors, and adhesion factors. Presenilin 1, the catalytic subunit of γ-secretase, associates with the cadherin/catenin cell-cell adhesion/communication system and promotes cadherin processing (Georgakopoulos, A., et al. (1999) Mol. Cell 4, 893–902; Marambaud, P., et al. (2002) EMBO J. 21, 1948–1956), but the mechanism by which γ-secretase and cadherins associate is unclear. Here we report that p120 catenin (p120ctn), a component of the cadherin-catenin complex, recruits γ-secretase to cadherins, thus stimulating their processing while inhibiting production of Aβ peptide and the amyloid precursor protein intracellular domain. This function of p120ctn depends on both p120ctn-cadherin and p120ctn-presenilin 1 binding, indicating that p120ctn is the central factor that bridges γ-secretase and cadherin-catenin complexes. Our data show that p120ctn is a unique positive regulator of the γ-secretase processing of cadherins and a negative regulator of the amyloid precursor protein processing. Furthermore, our data suggest that specific members of the γ-secretase complex may be used to recruit different substrates and that distinct PS1 sequences are required for processing of APP and cadherins