Abstract
Inward rectifier potassium ion channels (IK1-channels) of the Kir2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. IK1-channel loss-of-function, either congenital or acquired, has been associated with cardiac disease. Currently, basic research and specific treatment are hindered by the absence of specific and efficient Kir2.x channel activators. However, twelve different compounds, including approved drugs, show off-target IK1 activation. Therefore, these compounds contain valuable information towards the development of agonists of Kir channels, AgoKirs. We reviewed the mechanism of IK1 channel activation of these compounds, which can be classified as direct or indirect activators. Subsequently, we examined the most viable starting points for rationalized drug development and possible safety concerns with emphasis on cardiac and skeletal muscle adverse effects of AgoKirs. Finally, the potential value of AgoKirs is discussed in view of the current clinical applications of potentiators and activators in cystic fibrosis therapy.
Highlights
Kir2.x potassium channels are part of the inward rectifier K+ (IK1) channels family, which are of major importance for stabilizing the resting membrane potential of excitable cells and contribute to final action potential repolarization in cardiomyocytes [1,2]
IK1 has an important role in non-excitable cells, for example, in osteoblasts, in which IK1 channels are involved in chondrogenesis and osteoblastogenesis [3]
In human embryonic kidney 293 cells and Chinese hamster ovary (CHO) cells, ZAC increased IK1 carried by ectopic homotetrameric Kir2.1 channels but not current carried by homotetrameric Kir2.2 or Kir2.3 channels or heterotetrameric channels containing Kir2.1, Kir2.2, or Kir2.3 [40,57]
Summary
Tenidap is a non-steroidal cyclooxygenase and lipoxygenase inhibitor [48] and a potent Kir2.3 opener. By use of 86Rb+ cell efflux and patch clamp electrophysiology, it was found that tenidap increased Kir2.3 carried inward and outward current in Chinese hamster ovary (CHO) cells [44]. Tenidap showed some channel specificity as it did not enhance Kir2.1 and Kv1.5 channel activity [44]; it did activate IKATP channels [49]
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