BKCa Channels as Targets for Cardioprotection

Abstract

The large-conductance calcium- and voltage-activated K⁺ channel (BK_Ca) are encoded by the Kcnma1 gene. They are ubiquitously expressed in neuronal, smooth muscle, astrocytes, and neuroendocrine cells where they are known to play an important role in physiological and pathological processes. They are usually localized to the plasma membrane of the majority of the cells with an exception of adult cardiomyocytes, where BK_Ca is known to localize to mitochondria. BK_Ca channels couple calcium and voltage responses in the cell, which places them as unique targets for a rapid physiological response. The expression and activity of BK_Ca have been linked to several cardiovascular, muscular, and neurological defects, making them a key therapeutic target. Specifically in the heart muscle, pharmacological and genetic activation of BK_Ca channels protect the heart from ischemia-reperfusion injury and also facilitate cardioprotection rendered by ischemic preconditioning. The mechanism involved in cardioprotection is assigned to the modulation of mitochondrial functions, such as regulation of mitochondrial calcium, reactive oxygen species, and membrane potential. Here, we review the progress made on BK_Ca channels and cardioprotection and explore their potential roles as therapeutic targets for preventing acute myocardial infarction.

Keywords: BKCa channels; acute myocardial infarction; cardioprotection; ischemia-perfusion injury; mitochondria; potassium channels; reactive oxygen species.

Figure 1

BK_Ca signaling in cardiomyocytes mitochondria during ischemia-reperfusion (I/R) injury. I/R injury causes an increase of reactive oxygen species (ROS) production and Ca²⁺ overload that leads to mPTP opening, the collapse of membrane potential (ΔΨ_IMM), and the release of cytochrome C that causes cell death. The opening of BK_Ca protects the heart by reducing ROS and increasing the calcium retention capacity, hence delaying the opening of mPTP. IMM—Inner mitochondria membrane, OMM—Outer mitochondria membrane. mitoBK_Ca activators (NS1619, NS11021), mitoBK_Ca inhibitors (PAX-paxilline, IbTX-iberiotoxin), mPTP-mitochondrial permeability transition pore.

Figure 2

Structural formulas of commonly used mitochondrial BK_Ca modulators.