Abstract
The complex interplay of ion channels within biological systems holds profound implications for physiological function and pathology. Among these channels, the KIR2.1 channel plays pivotal roles in cellular processes, ranging from membrane potential maintenance to cardiac excitability regulation. Chapter 2 made a comprehensive exploration of the KIR2.1 channel, covering its
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functions, trafficking mechanisms, and its connections to various diseases. As for patients who suffer from the dysfunction of KIR2.1 channels, it is essential to develop new drugs. Central to this inquiry, propafenone emerges as a notable player. While recognized as an agonist for the KIR2.1 channel, propafenone’s efficacy is overshadowed by significant off-target effects, particularly the blockade of the NaV1.5 channel (its primary target), and intracellular KIR2.1 channel and Cx43 protein accumulation (Chapter 3 and Chapter 4). These off-target effects emphasize the necessity for the development of KIR2.1 channel openers with increased specificity and efficiency. Chapter 5 introduces GPV0057 as a promising analogue that addresses the limitations of propafenone. It has shown efficacy with reduced adverse effects and holds the potential for mitigating IK1 reduction in heart failure (HF) and Andersen-Tawil syndrome (ATS), indicating its clinical relevance in cardiac pathologies. However, despite these encouraging findings, the journey towards clinical translation remains incomplete yet. Additional research is necessary to confirm the effectiveness of GPV0057 in relevant pathological contexts, especially in failing hearts and cells that contain ATS mutations. In addition to pharmacological modulation, the process of channel trafficking plays an essential role in governing the function and regulation of ion channels. The correct trafficking of the KIR2.1 channel is crucial for its localization, assembly into functional complexes, and activity regulation. In Chapter 6, we quantified the influence of the cytoskeleton on KIR2.1 trafficking. Our results indicate that the functionality of the cytoskeleton does not hinder the planar movement of the channel, and there is no alteration in the overall expression of channel proteins. We found that forward trafficking of KIR2.1 depends on intact actin and tubulin. Additionally, we observed a reliance of KIR2.1 backward trafficking on cytoskeletal dynamics. Finally, in Chapter 7, we summarized and discussed the results and conclusions from previous chapters. This thesis examines the KIR2.1 channel, focusing on its functions, trafficking, associated diseases, and pharmacology. Propafenone is identified as an agonist for the KIR2.1 channel but with significant off-target effects, including NaV1.5 channel blockade and intracellular protein accumulation (KIR2.1 and Cx43). GPV0057, a propafenone analogue, shows promise with enhanced IK1 current and with fewer side effects. It may mitigate IK1 reduction in HF or ATS. However, further investigation is required to validate its efficacy in failing hearts and ATS mutants.
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