WNK-dependent phosphorylation of gephyrin tunes GABA A receptors at inhibitory synapses and modulates anxiety behavior
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.
Authors
- Joëlle Vinh (ORCID: https://orcid.org/0000-0001-7184-2668)
- Marika Nosten‐Bertrand (ORCID: https://orcid.org/0000-0001-7593-1959)
- Yann Verdier (ORCID: https://orcid.org/0000-0002-3319-0053)
- Zaha Merlaud (ORCID: https://orcid.org/0000-0003-1378-3035)
- Sabine Lévi (ORCID: https://orcid.org/0000-0002-9927-0945)
- Corentin Le Magueresse (ORCID: https://orcid.org/0000-0001-8418-4991)
- Maelys Tostain
- Juliette Gouhier (ORCID: https://orcid.org/0000-0002-9811-7260)
- Célia Delhaye
- Marion Russeau (ORCID: https://orcid.org/0000-0002-9681-0491)
- Erwan Pol (ORCID: https://orcid.org/0009-0004-5291-7192)
- Nalia Samba (ORCID: https://orcid.org/0009-0005-7822-9440)
- Zahra Imani
- Margarida Nabais
- Romane Rahir
- Tânia Lima (ORCID: https://orcid.org/0009-0008-7643-7125)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Chimie ParisTech - PSL (FR)
- Inserm (FR)
- Sorbonne Université (FR)
- Institut de Biologie Paris-Seine (FR)
- Institut du Fer à Moulin (FR)
- Université Paris 1 Panthéon-Sorbonne (FR)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-08-25
- DOI
- https://doi.org/10.1073/pnas.2612761123
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Université de Recherche Paris Sciences et Lettres
- Sorbonne Université
- Institut des sciences biologiques