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

Nicolas H. Piguel, Shaun S. Sanders, Francesca I. De Simone, Maria D. Martin-de-Saavedra, Emmarose McCoig, Leonardo E. Dionisio, Katharine R. Smith, Gareth M. Thomas, Peter Penzes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Introduction: AnkG, encoded by the ANK3 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 ANK3 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. Result: 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. Discussion: 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.

Original languageEnglish (US)
Article number1144066
JournalFrontiers in Molecular Neuroscience
StatePublished - 2023


  • ANK3
  • ZDHHC8
  • ankyrin-G
  • dendrite
  • dendritic spine
  • lithium
  • palmitoylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience


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