Key result
SNX17 mediates susceptibility to atrial fibrillation by regulating endocytic sorting of the Kv1.5 channel through the FERM domain.
Why the study?
Kv1.5 is considered a promising target for AF interventions, but whether SNX17 regulates the trafficking process of Kv1.5 remains unknown.
SNX17 regulates the endocytic sorting of the Kv1.5 channel, and its deficiency increases susceptibility to atrial fibrillation, highlighting it as a potential therapeutic target.
SNX17 may represent a novel AF target; leaves open translation from this animal model to human therapy.
BACKGROUND: Kv1.5 (Potassium voltage-gated channel subfamily A member 5) has been regarded as a promising target of interventions for atrial fibrillation (AF). SNX17 (sorting nexin 17), a member of the SNXs (sorting nexin family), regulates the intracellular trafficking of membrane proteins through its FERM (four-point-one, ezrin, radixin, moesin) domain. However, whether SNX17 regulates the trafficking process of Kv1.5 remains unknown. METHODS: A SNX17 knockout rat line was generated to test the role of SNX17 in atrial electrophysiology. The protein expression of SNX17 and membrane ion channels was detected by Western blotting. Electrophysiology changes in the atrial tissue and myocytes were analyzed by optical mapping and patch clamp, respectively. Acetylcholine and electrical stimulation were used to induce AF, and ECG recording was adopted to assess the influence of SNX17 deficiency on AF susceptibility. The spatial relationship between Kv1.5 and SNX17 was evaluated by immunostaining and confocal scanning, and the functional region of SNX17 regulating Kv1.5 trafficking was identified using plasmids with truncated SNX17 domains. RESULTS: ) density, resulting in a shortened action potential duration, and eventually contributing to AF susceptibility. Mechanistically, SNX17 facilitated the endocytic sorting of Kv1.5 from the plasma membrane to early endosomes via the FERM domain. CONCLUSIONS: SNX17 mediates susceptibility to AF by regulating endocytic sorting of the Kv1.5 channel through the FERM domain. SNX17 could be a potential target for the development of new drugs for AF.
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Li et al. (2019) studied Atrial fibrillation. SNX17 knockout was evaluated on Atrial fibrillation susceptibility and Kv1.5 channel trafficking. SNX17 mediates susceptibility to atrial fibrillation by regulating endocytic sorting of the Kv1.5 channel through the FERM domain.
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