Year: 2026
Type: article
Abstract: Introduction: Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of neuronal expression of the E3 ubiquitin ligase UBE3A and is associated with altered neuronal excitability. We previously identified the dendritic A-type K+ channel subunit Kv4.2 as an activity-dependent substrate of UBE3A. However, where UBE3A interacts with Kv4.2 during activity-dependent trafficking and how this pathway regulates Kv4.2 channel complexes and dendritic distribution remain unclear.. Methods: We combined live-cell bungarotoxin labeling and biochemical surface-labeling approaches to examine UBE3A association with surface-derived Kv4.2. Co-immunoprecipitation and immunoblotting were used to assess Kv4.2 association with the auxiliary subunit DPP6 and activity-dependent Kv4.2 phosphorylation in wild-type (WT), UBE3A-deficient (AS), and DPP6 knockout (KO) mice. Kv4.2 immunostaining and quantitative line-scan analysis were used to examine its proximal-to-distal distribution in hippocampal CA1 dendrites. Results: UBE3A preferentially associated with internalized rather than surface-resident Kv4.2, supporting a post-endocytic site of UBE3A action. In AS mice, Kv4.2-DPP6 association was reduced and failed to undergo further activity-dependent remodeling following pentylenetetrazole (PTZ)-induced seizures, despite unchanged DPP6 expression and preserved basal Kv4.2 phosphorylation. In contrast, DPP6 deficiency increased basal Kv4.2 phosphorylation at T602 and T607 and disrupted its activity-dependent phosphorylation dynamics, indicating reciprocal regulation between Kv4.2 phosphorylation and DPP6 association. DPP6KO mice exhibited impaired Kv4.2 gradients along both apical and basal CA1 dendrites. Similarly, AS mice showed impaired dendritic Kv4.2 gradients and reduced activity-dependent redistribution following kainic acid-induced seizures. Conclusion: These findings support a model in which neuronal activity promotes remodeling and internalization of Kv4.2-containing channel complexes, followed by UBE3A-dependent processing of the post-endocytic Kv4.2 pool. Loss of UBE3A disrupts Kv4.2-DPP6 complex dynamics and dendritic Kv4.2 organization, thereby reducing the capacity for activity-dependent channel redistribution. These results identify UBE3A as an important regulator of Kv4.2 homeostasis and provide a mechanistic link between UBE3A deficiency, altered dendritic ion-channel organization, and neuronal dysfunction in Angelman syndrome.
Authors: Jia-Hua Hu, Ying Liu, Cole Malloy, Dax A. Hoffman
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223092713