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The Ubiquitin Ligase Adaptor NDFIP1 Interacts with TRESK and Negatively Regulates the Background K+ Current
Enikő Pergel1, Dániel J Tóth1,2, Dóra Baukál1
1Department of Physiology, Semmelweis University, 1094 Budapest, Hungary.
International Journal of Molecular Sciences
|August 29, 2024
Summary
The Nedd4 family-interacting protein 1 (NDFIP1) regulates the TRESK potassium channel, crucial for pain sensation. NDFIP1, via the Nedd4 ubiquitin ligase, reduces TRESK activity, impacting neuronal excitability.
Area of Science:
- Molecular and Cellular Biology
- Neuroscience
- Ion Channel Physiology
Background:
- The TRESK (K2P18.1, KCNK18) potassium channel is implicated in regulating pain sensations.
- TRESK is expressed in primary sensory neurons, highlighting its role in nociception.
Purpose of the Study:
- To investigate the interaction between TRESK and Nedd4 family-interacting protein 1 (NDFIP1).
- To elucidate the functional consequences of this interaction on TRESK channel activity.
Main Methods:
- Utilized the Xenopus oocyte expression system.
- Employed two-electrode voltage clamp electrophysiology.
- Conducted biochemical analyses, including co-immunoprecipitation and ubiquitination assays.
Main Results:
- Coexpression of NDFIP1 significantly abolished TRESK current without affecting other potassium channels.
- Mutations in NDFIP1's PPxY motifs abolished the reduction in TRESK current, indicating Nedd4 dependence.
- Overexpression of dominant-negative Nedd4 partially reversed NDFIP1's inhibitory effect on TRESK.
Conclusions:
- TRESK activity is directly modulated by the NDFIP1-Nedd4 ubiquitin ligase system.
- NDFIP1 induces TRESK ubiquitination, leading to reduced channel activity.
- The NDFIP1-mediated downregulation of TRESK may influence neuronal excitability and pain signaling.
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