Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps University Marburg, Marburg, Germany.
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Philipps-University Marburg, Marburg, Germany.
Nat Commun. 2024 Aug 30;15(1):7548. doi: 10.1038/s41467-024-51288-8.
TASK-5 (KCNK15) belongs to the acid-sensitive subfamily of two-pore domain potassium (K) channels, which includes TASK-1 and TASK-3. TASK-5 stands out as K channel for which there is no functional data available, since it was reported in 2001 as non-functional and thus "silent". Here we show that TASK-5 channels are indeed non-functional as homodimers, but are involved in the formation of functional channel complexes with TASK-1 and TASK-3. TASK-5 negatively modulates the surface expression of TASK channels, while the heteromeric TASK-5-containing channel complexes located at the plasma membrane are characterized by changes in single-channel conductance, Gq-coupled receptor-mediated channel inhibition, and sensitivity to TASK modulators. The unique pharmacology of TASK-1/TASK-5 heterodimers, affected by a common polymorphism in KCNK15, needs to be carefully considered in the future development of drugs targeting TASK channels. Our observations provide an access to study TASK-5 at the functional level, particularly in malignant cancers associated with KCNK15.
任务 5（KCNK15）属于双孔域钾（K）通道的酸敏感亚家族，其中包括 TASK-1 和 TASK-3。TASK-5 是唯一没有功能数据的 K 通道，因为它在 2001 年被报道为非功能性的，因此是“沉默的”。在这里，我们表明 TASK-5 通道实际上作为同源二聚体是无功能的，但参与与 TASK-1 和 TASK-3 形成功能性通道复合物。TASK-5 负调节 TASK 通道的表面表达，而位于质膜上的含有异源二聚体 TASK-5 的通道复合物的特征在于单通道电导、Gq 偶联受体介导的通道抑制以及对 TASK 调节剂的敏感性的变化。需要在未来靶向 TASK 通道的药物开发中仔细考虑 TASK-1/TASK-5 异源二聚体的独特药理学，其受 KCNK15 中的常见多态性影响。我们的观察结果为在功能水平上研究 TASK-5 提供了一种途径，特别是在与 KCNK15 相关的恶性癌症中。
