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Palmitoylation of A-Kinase Anchoring Protein 79/150 Regulates Dendritic Endosomal Targeting and Synaptic Plasticity Mechanisms
Open accessAbstract
NMDA receptor-dependent long-term potentiation (LTP) and depression (LTD) are forms of synaptic plasticity underlying learning and memory that are expressed through increases and decreases, respectively, in dendritic spine size and AMPA receptor (AMPAR) phosphorylation and postsynaptic localization. The A-kinase anchoring protein 79/150 (AKAP79/150) signaling scaffold regulates AMPAR phosphorylation, channel activity, and endosomal trafficking associated with LTP and LTD. AKAP79/150 is targeted to dendritic spine plasma membranes by an N-terminal polybasic domain that binds phosphoinositide lipids, F-actin, and cadherin cell adhesion molecules. However, we do not understand how regulation of AKAP targeting controls AMPAR endosomal trafficking. Here, we report that palmitoylation of the AKAP N-terminal polybasic domain targets it to postsynaptic lipid rafts and dendritic recycling endosomes. AKAP palmitoylation was regulated by seizure activity in vivo and LTP/LTD plasticity-inducing stimuli in cultured rat hippocampal neurons. With chemical LTP induction, we observed AKAP79 dendritic spine recruitment that required palmityolation and Rab11-regulated endosome recycling coincident with spine enlargement and AMPAR surface delivery. Importantly, a palmitoylation-deficient AKAP79 mutant impaired regulation of spine size, endosome recycling, AMPAR trafficking, and synaptic potentiation. These findings emphasize the emerging importance of palmitoylation in controlling synaptic function and reveal novel roles for the AKAP79/150 signaling complex in dendritic endosomes.
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“our recent published findings indicated that AKAP79/150 palmitoylation targets it to dendritic recycling endosomes in cultured neurons to specifically control GluA1 trafficking and Ca2+-permeable AMPAR synaptic activity”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors (2012) · cites this paper as Keith et al., 2012
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“This AKAP removal from synapses is caused by inhibition of N-terminal targeting interactions through depalmitoylation, phospholipase C cleavage of PIP2, and CaN-dependent actin depolymerization”
From AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors (2012) · cites this paper as Keith et al., 2012
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Cites
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Self-citationReinsertion or Degradation of AMPA Receptors Determined by Activity-Dependent Endocytic Sorting
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PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity
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Recycling Endosomes Supply AMPA Receptors for LTP
Park, M., Penick, E. C., Edwards, J. G., Kauer, J. A., & Ehlers, M. D. (2004) · Science · doi:10.1126/science.1102026 · Cited by 730
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Lucero, E., Freund, R. K., Johnson, N. R., Dooling, B. R., Sullivan, E. M., Prikhodko, O., Ahmed, M. M., Dell’Acqua, M. L., Chial, H. J., & Potter, H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.09.459627
Self-citationLucero, E., Freund, R. K., Smith, A. N., Johnson, N., Dooling, B. R., Sullivan, E. M., Prikhodko, O., Ahmed, M. M., Bennett, D. A., Hohman, T. J., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4050072
Self-citationSuppression of AKAP150 palmitoylation alleviates seizures in kainic acid-induced epilepsy mice
Chu, C.-C., Hu, Y.-H., Zhang, H., Li, G.-Z., Wu, S., Zang, Y., Chen, J., Wang, H., Xu, Y.-Y., Guo, H.-L., et al. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.10.061
The Scrib1 Interactome and its relevance for synaptic plasticity & neurodevelopmental disorders
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Role of vSNAREs in post-synaptic AMPAR trafficking, glutamatergic transmisson and plasticity
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Learning-specific remodeling of the hippocampal palmitoylomePreprint
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Anchored kinase and phosphatase signaling networks in amyloid β-induced synaptic dysfunction
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Self-citationNanoscale Architecture Can Control Cellular Function.
Lee, H. N., Qiao, L., Zhong, Y.-H., Mehta, S., Nishida, A., Rangamani, P., & Zhang, J. (2026) · ACS Nano · doi:10.1021/acsnano.6c03529
Metadata
- Authors
- Keith, D. J., Sanderson, J. L., Gibson, E. S., Woolfrey, K. M., Robertson, H. R., Olszewski, K., Kang, R., El-Husseini, A., & Dell'Acqua, M. L.
- Affiliations
- University of Colorado Anschutz (US)
- University of Colorado Denver (US)
- Massachusetts Institute of Technology (US)
- University of British Columbia (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-05-23
- Volume
- 32
- Issue
- 21
- Pages
- 7119-7136
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3367663
- OpenAlex
- W2083102450
- Cited by
- 108
- References
- 65
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 9 · 2019: 11 · 2018: 11 · 2017: 9 · 2016: 5 · 2015: 9 · 2014: 10 · 2013: 9 · 2012: 2
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Michael Smith Health Research BC
- National Institutes of Health (5t32ns007083-27)
- Anschutz Medical Campus, University of Colorado (P30 NS048154)
- Canadian Institutes of Health Research (MOP81144, MOP44052, 20R90479, 20R91909)
- National Institute on Alcohol Abuse and Alcoholism (T32AA007464)
- National Institute of General Medical Sciences (T32GM007635)
- National Institute of Neurological Disorders and Stroke (P30NS048154, T32-NS-007083, R01NS040701)
- National Center for Research Resources (UL1RR025780)
- National Center for Complementary and Integrative Health (T32AT002688)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- AKAP79/150, palmitoylation, long-term depression, synaptic plasticity, AMPA receptor trafficking, endosomal recycling, lipid rafts, Rab11, seizure activity, hippocampal neurons, polybasic domain, postsynaptic signaling
- MeSH terms
- Animals, Cells, Cultured, Chlorocebus aethiops, Dendrites, Female, Hippocampus, Kainic Acid, Male, Neuronal Plasticity, Endosomes, Seizures, Rats, Sprague-Dawley, Rats, Wistar, Long-Term Potentiation, Receptors, AMPA, COS Cells, Protein Transport, Long-Term Synaptic Depression, Dendritic Spines, Rats, A Kinase Anchor Proteins, Lipoylation, Gene Knockdown Techniques
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