A distinct PP2A subunit regulates local protein phosphorylation at the axon initial segment

Andrew P. Anderson, Sanghyun Kim, Allison J. Melton, Xiaoyun Ding, Wei Zhang, Alexander B. Saltzman, Anna Malovannaya, Matthew N. Rasband and Yudong Gao ()
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Andrew P. Anderson: Baylor College of Medicine, Department of Neuroscience
Sanghyun Kim: Baylor College of Medicine, Department of Neuroscience
Allison J. Melton: Baylor College of Medicine, Department of Neuroscience
Xiaoyun Ding: Baylor College of Medicine, Department of Neuroscience
Wei Zhang: Baylor College of Medicine, Department of Neuroscience
Alexander B. Saltzman: Baylor College of Medicine, Mass Spectrometry Proteomics Core
Anna Malovannaya: Baylor College of Medicine, Mass Spectrometry Proteomics Core
Matthew N. Rasband: Baylor College of Medicine, Department of Neuroscience
Yudong Gao: Baylor College of Medicine, Department of Neuroscience

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Protein phosphorylation plays a crucial role in regulating the cytoskeletal and membrane proteins at the axon initial segment (AIS). However, our knowledge of AIS-specific kinases and phosphatases is very limited. Here, we report the identification of a protein phosphatase 2A (PP2A) B55 regulatory subunit enriched at the AIS in mice: Ppp2r2c. Our results demonstrate that PP2A-B55 subunits exhibit substantial heterogeneity in their subcellular localization and function. Notably, the Ppp2r2c subunit is selectively concentrated at the AIS, and this enrichment is driven by its unique structure. Utilizing a microelectrode array system (MEA), we show that Ppp2r2c modulates neuronal activity during in vitro development. With phosphoproteomics, we further reveal that the potassium channel Kv1.2 is one of the downstream targets that link Ppp2r2c activity to neuronal excitability. Together, these data provide a critical entry point for understanding the mechanisms of PP2A-mediated local phospho-regulation at the AIS.

Date: 2025
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DOI: 10.1038/s41467-025-66120-0

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