Li Encan, Kool Willy, Woolschot Liset, van der Heyden Marcel A G
Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands.
Pharmaceuticals (Basel). 2023 Mar 7;16(3):404. doi: 10.3390/ph16030404.
Expression and activity of inwardly rectifying potassium (K) channels within the heart are strictly regulated. K channels have an important role in shaping cardiac action potentials, having a limited conductance at depolarized potentials but contributing to the final stage of repolarization and resting membrane stability. Impaired K2.1 function causes Andersen-Tawil Syndrome (ATS) and is associated with heart failure. Restoring K2.1 function by agonists of K2.1 (AgoKirs) would be beneficial. The class 1c antiarrhythmic drug propafenone is identified as an AgoKir; however, its long-term effects on K2.1 protein expression, subcellular localization, and function are unknown. Propafenone's long-term effect on K2.1 expression and its underlying mechanisms in vitro were investigated. K2.1-carried currents were measured by single-cell patch-clamp electrophysiology. K2.1 protein expression levels were determined by Western blot analysis, whereas conventional immunofluorescence and advanced live-imaging microscopy were used to assess the subcellular localization of K2.1 proteins. Acute propafenone treatment at low concentrations supports the ability of propafenone to function as an AgoKir without disturbing K2.1 protein handling. Chronic propafenone treatment (at 25-100 times higher concentrations than in the acute treatment) increases K2.1 protein expression and K2.1 current densities in vitro, which are potentially associated with pre-lysosomal trafficking inhibition.
心脏内向整流钾（K）通道的表达和活性受到严格调控。K通道在塑造心脏动作电位方面发挥着重要作用，在去极化电位时电导有限，但有助于复极化的最后阶段和静息膜稳定性。K2.1功能受损会导致安德森-塔维尔综合征（ATS），并与心力衰竭相关。通过K2.1激动剂（AgoKirs）恢复K2.1功能将是有益的。1c类抗心律失常药物普罗帕酮被鉴定为一种AgoKir；然而，其对K2.1蛋白表达、亚细胞定位和功能的长期影响尚不清楚。研究了普罗帕酮在体外对K2.1表达的长期影响及其潜在机制。通过单细胞膜片钳电生理学测量K2.1携带的电流。通过蛋白质免疫印迹分析确定K2.1蛋白表达水平，而传统免疫荧光和先进的活细胞成像显微镜用于评估K2.1蛋白的亚细胞定位。低浓度急性普罗帕酮处理支持普罗帕酮作为AgoKir发挥作用的能力，而不会干扰K2.1蛋白的处理。慢性普罗帕酮处理（浓度比急性处理高25至100倍）可增加体外K2.1蛋白表达和K2.1电流密度，这可能与溶酶体前运输抑制有关。
