KCTD1 regulation of Adenylyl cyclase type 5 adjusts striatal cAMP signaling

• 成果类型: Article
• 署名作者: Liao, Yini; Muntean, Brian S.
• 署名单位: University System of Georgia; Augusta University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9722
• DOI: 10.1073/pnas.2406686121
• 发表日期: 2024-10-22
• 关键词: de-novo mutations; basal ganglia; synaptic-transmission; point mutation; gene; dopamine; modulation; expression; plasticity; identification

摘要

Dopamine transfers information to striatal neurons, and disrupted neurotransmission leads to motor deficits observed in movement disorders. Striatal dopamine converges the essential role of signal transduction in motor physiology. However, the relationship between dopamine decoding and AC5 regulation is unknown. Here, we utilized an unbiased global protein stability screen to identify Potassium Channel Tetramerization Domain 1 (KCTD1) as a key regulator of AC5 level that is mechanistically tied to N- linked glycosylation. We then implemented a CRISPR/SaCas9 approach to eliminate KCTD1 in striatal neurons expressing a F & ouml;rster resonance energy transfer (FRET)- based cAMP biosensor. 2- photon imaging of striatal neurons in intact circuits uncovered that dopaminergic signaling was substantially compromised in the absence of KCTD1. Finally, knockdown of KCTD1 in genetically defined dorsal striatal neurons significantly altered motor behavior in mice. These results reveal that KCTD1 acts as an essential modifier of dopaminergic signaling by stabilizing striatal AC5.