Stabilization of ion channel protein by regulation of proteasome and its application to the individualizing atrial fibrillation.

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Background : Previously we reported that ion channels responsible for chronic atrial fibrillation have been degraded by ubiquitin-proteasome, which was modification by antiarrhythmic agents. In the current study, we elucidated its underlying mechanism and application to the individualizing therapy for atrial fibrillation.Methods and Results : Na^+ channel blockers, but not either Ca^<2+> antagonists or K^+ channel blockers, blocked 20S proteasome activity to stabilize the short-lived proteins including p53,IKK2 and Kv1.5 assessed by pulse-chase analysis, immnofluorescence and patch clamp techniques in transfected COS cells. To confirm that p53 stabilization by Na^+ channel blockers was secondary to proteasome inhibition, we examined whether Mdm2 (C438A) could block the drug effects. When co-expressed with Mdm2 (C438A), p53-FLAG was not at all ubiquitinated even when cells were treated with MG132 and this drug failed to increase the p53-FLAG protein level. Likewise, p53-FLAG was not ubiquitinated in cells treated with Na^+ channel blockers, which failed to increase the protein level. Na^+ channel blockers stabilized the short-lived Kir6.2 channel proteins like MG132. There were several SNPs on the lysine residues in the coding region of Kir6.2, suggesting SNPs can affect the extent of channel protein degradation.Conclusion : Expression of short-lived ion channels have been regulated by ubiquitin-proteasome, which can be modulated by Na^+ channel blockers. Based on the SNPs information, a pharmacological therapy to regulate proteasomal degradation of channel protein can be available for treating the patients with chronic atrial fibrillation.