Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium

• Published in: Frontiers in molecular neuroscience 2023-03, Vol.16, p.1144066-1144066
• Main Authors: Piguel, Nicolas H, Sanders, Shaun S, De Simone, Francesca I, Martin-de-Saavedra, Maria D, McCoig, Emmarose, Dionisio, Leonardo E, Smith, Katharine R, Thomas, Gareth M, Penzes, Peter
• Format: Article
• Language: English
• Subjects: ANK3; ankyrin-G; Ankyrins; Antibodies; Bipolar disorder; Cloning; dendrite; dendritic spine; Dendritic spines; Isoforms; Lipid membranes; Lithium; Localization; Mental disorders; Microscopy; Mobility; Molecular Neuroscience; Neurodevelopmental disorders; Neurons; Palmitoylation; Plasmids; Post-translation; Postsynaptic density proteins; Proteins
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2023.1144066

AnkG, encoded by the gene, is a multifunctional scaffold protein with complex isoform expression: the 480 and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, whereas the 190 kDa isoform (AnkG-190) has an emerging role in the dendritic shaft and spine heads. All isoforms of AnkG undergo palmitoylation, a post-translational modification regulating protein attachment to lipid membranes. However, palmitoylation of AnkG-190 has not been investigated in dendritic spines. The gene and altered expression of AnkG proteins are associated with a variety of neuropsychiatric and neurodevelopmental disorders including bipolar disorder and are implicated in the lithium response, a commonly used mood stabilizer for bipolar disorder patients, although the precise mechanisms involved are unknown. Here, we showed that Cys70 palmitoylation stabilizes the localization of AnkG-190 in spine heads and at dendritic plasma membrane nanodomains. Mutation of Cys70 impairs AnkG-190 function in dendritic spines and alters PSD-95 scaffolding. Interestingly, we find that lithium reduces AnkG-190 palmitoylation thereby increasing its mobility in dendritic spines. Finally, we demonstrate that the palmitoyl acyl transferase ZDHHC8, but not ZDHHC5, increases AnkG-190 stability in spine heads and is inhibited by lithium. Together, our data reveal that palmitoylation is critical for AnkG-190 localization and function and a potential ZDHHC8/AnkG-190 mechanism linking AnkG-190 mobility to the neuronal effects of lithium.