Mitochondrial Potassium Channels as Druggable Targets.

Antoni Wrzosek,Bartłomiej Augustynek,Adam Szewczyk,Monika Żochowska

doi:10.3390/biom10081200

Abstract

Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper.

Highlights

The mitochondrial potassium channels field started in the beginning of the 1990s when the first paper describing potassium channel sensitive to ATP and antidiabetic sulphonylurea–glibenclamide was described [1]
We have described our current understanding of the interactions of numerous drugs with mitochondrial potassium channels
We have described the secondary effects of the drugs in addition to their interaction with their primary target i.e., mitochondrial potassium channels

Summary

Introduction

The mitochondrial potassium channels field started in the beginning of the 1990s when the first paper describing potassium channel sensitive to ATP and antidiabetic sulphonylurea–glibenclamide (mitoKATP channel) was described [1]. The finding of calcium-activated large conductance channel in inner mitochondrial membrane (mitoBKCa) would not help position potassium channel in mitochondrial function [2]. The discovery that activation of the mitochondrial potassium channel by potassium channel openers induces protective mechanisms in cardiac myocytes positioned these proteins as an important player in ischemic preconditioning [3] This was a starting point for trials to target various mitochondrial potassium channels with drugs to affect cell life. The BKCa channels, which are highly abundant in the cell membrane of various cells, are present in only the inner mitochondrial membrane (mitoBKCa channels) but not in plasma membrane of cardiomyocytes [14] This observation is notably unique for mitochondrial potassium channels and may support that mitochondrial potassium channels and cardiac tissue are druggable targets. This uneven distribution of mitoBKCa channels and the functional consequences of the intracellular heterogeneity of mitochondrial potassium channels still need to be elucidated

Plasma Membrane Versus Mitochondrial Potassium Channels

Unique Regulation of Mitochondrial Potassium Channels

Off-Target Action and Drug Repositioning of Potassium Channel Modulators

Concluding Remarks