Skip to Content
Merck
  • Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning.

Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning.

Cell reports (2022-12-09)
Jens Stepan, Daniel E Heinz, Frederik Dethloff, Thomas Bajaj, Andreas Zellner, Kathrin Hafner, Svenja Wiechmann, Sarah Mackert, Yara Mecdad, Michael Rabenstein, Tim Ebert, Silvia Martinelli, Alexander S Häusl, Maximilian L Pöhlmann, Anke Hermann, Xiao Ma, Hermann Pavenstädt, Mathias V Schmidt, Alexandra Philipsen, Chris W Turck, Jan M Deussing, Bernhard Kuster, Michael C Wehr, Valentin Stein, Joachim Kremerskothen, Carsten T Wotjak, Nils C Gassen
ABSTRACT

Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) number, spatial organization, and function. The Hippo pathway component WW and C2 domain-containing protein 1 (WWC1) regulates AMPAR surface expression and impacts on memory performance. However, synaptic binding partners of WWC1 and its hierarchical position in AMPAR complexes are largely unclear. Using cell-surface proteomics in hippocampal tissue of Wwc1-deficient mice and by generating a hippocampus-specific interactome, we show that WWC1 is a major regulatory platform in AMPAR signaling networks. Under basal conditions, the Hippo pathway members WWC1 and large tumor-suppressor kinase (LATS) are associated, which might prevent WWC1 effects on synaptic proteins. Reduction of WWC1/LATS binding through a point mutation at WWC1 elevates the abundance of WWC1 in AMPAR complexes and improves hippocampal-dependent learning and memory. Thus, uncoupling of WWC1 from the Hippo pathway to AMPAR-regulatory complexes provides an innovative strategy to enhance synaptic transmission.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-DNM1 antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Anti-NRXN1 antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Sigma-Aldrich
Anti-PACSIN1 Antibody, NT, from rabbit
Sigma-Aldrich
Anti-BAIAP2 antibody produced in rabbit, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-DNAI1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, Ab2