Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium
IntroductionAnkG, 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 hea...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1144066/full |
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| author | Nicolas H. Piguel Shaun S. Sanders Francesca I. De Simone Maria D. Martin-de-Saavedra Maria D. Martin-de-Saavedra Emmarose McCoig Leonardo E. Dionisio Katharine R. Smith Gareth M. Thomas Peter Penzes Peter Penzes Peter Penzes |
| author_facet | Nicolas H. Piguel Shaun S. Sanders Francesca I. De Simone Maria D. Martin-de-Saavedra Maria D. Martin-de-Saavedra Emmarose McCoig Leonardo E. Dionisio Katharine R. Smith Gareth M. Thomas Peter Penzes Peter Penzes Peter Penzes |
| author_sort | Nicolas H. Piguel |
| collection | DOAJ |
| description | IntroductionAnkG, 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.ResultHere, 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.DiscussionTogether, 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. |
| first_indexed | 2024-04-10T05:22:19Z |
| format | Article |
| id | doaj.art-52a343df27d8423883a4ff7c95f0ced1 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-10T05:22:19Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-52a343df27d8423883a4ff7c95f0ced12023-03-08T06:11:27ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-03-011610.3389/fnmol.2023.11440661144066Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithiumNicolas H. Piguel0Shaun S. Sanders1Francesca I. De Simone2Maria D. Martin-de-Saavedra3Maria D. Martin-de-Saavedra4Emmarose McCoig5Leonardo E. Dionisio6Katharine R. Smith7Gareth M. Thomas8Peter Penzes9Peter Penzes10Peter Penzes11Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesShriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesShriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesDepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Biochemistry and Molecular Biology, School of Pharmacy, Instituto Universitario de Investigación en Neuroquímica, Complutense University of Madrid, Madrid, SpainDepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Pharmacology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesDepartment of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesNorthwestern University Center for Autism and Neurodevelopment, Chicago, IL, United StatesIntroductionAnkG, 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.ResultHere, 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.DiscussionTogether, 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.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1144066/fullANK3ankyrin-Gdendritedendritic spinepalmitoylationlithium |
| spellingShingle | Nicolas H. Piguel Shaun S. Sanders Francesca I. De Simone Maria D. Martin-de-Saavedra Maria D. Martin-de-Saavedra Emmarose McCoig Leonardo E. Dionisio Katharine R. Smith Gareth M. Thomas Peter Penzes Peter Penzes Peter Penzes Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium Frontiers in Molecular Neuroscience ANK3 ankyrin-G dendrite dendritic spine palmitoylation lithium |
| title | Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium |
| title_full | Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium |
| title_fullStr | Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium |
| title_full_unstemmed | Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium |
| title_short | Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium |
| title_sort | palmitoylation controls the stability of 190 kda ankyrin g in dendritic spines and is regulated by zdhhc8 and lithium |
| topic | ANK3 ankyrin-G dendrite dendritic spine palmitoylation lithium |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1144066/full |
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