WNK-dependent phosphorylation of gephyrin tunes GABA A receptors at inhibitory synapses and modulates anxiety behavior
- Zaha Merlaud
- Celia Delhaye
- Margarida Nabais
- Erwan Pol
- Tânia Lima
- Yann Verdier
- Zahra Imani
- Marion Russeau
- Nalia Samba
- Maelys Tostain
- Juliette Gouhier
- Romane Rahir
- Joelle Vinh
- Corentin Le Magueresse
- Marika Nosten-Bertrand
- Sabine Lévi
2026-08-25
The role of the chloride-sensitive kinase WNK1 and its effector SPAK in the brain remains poorly understood. Here, we identify a WNK-dependent regulatory mechanism that directly controls the synaptic diffusion and clustering of inhibitory GABA A receptors (GABA A Rs), as well as their membrane stability and endocytosis. We show that activation of WNK signaling stabilizes GABA A Rs at inhibitory synapses, while inhibition enhances receptor internalization. This regulation depends on the phosphorylation state of two residues in the central linker region of the gephyrin scaffold protein. Modulating WNK activity alters neuronal activity and the kinetics of GABAergic currents. In vivo, expression of a phospho-mimetic form of gephyrin at WNK-targeted sites produces anxiolytic-like effects. Together with prior evidence showing that WNK signaling regulates the chloride transporters KCC2 and NKCC1, key determinants of intracellular chloride homeostasis and GABAergic efficacy, our findings position the WNK pathway as a master regulator of inhibitory synapse function.