BKCa Channels as Targets for Cardioprotection

Abstract

The large-conductance calcium- and voltage-activated K+ channel (BKCa) 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 BKCa is known to localize to mitochondria. BKCa 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 BKCa 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 BKCa 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 BKCa channels and cardioprotection and explore their potential roles as therapeutic targets for preventing acute myocardial infarction.

Mitochondrial Dysfunction and Heart Disease: Critical Appraisal of an Overlooked Association

“…Interestingly, a large conductance, calcium-activated K + channel (BK Ca ), expressed on the plasma membrane of most cell types but characteristically found on the inner mitochondrial membrane of adult cardiomyocytes (mitoBK Ca ), has been shown to confer protection from IRI by increasing the mitochondrial calcium capacity and reducing ROS production [ 36 ]. Increased ROS production during preconditioning triggers the opening of the mitoBK Ca channel, leading to a K + influx in mitochondria with an ensuing reduction in Ca 2+ influx and internal membrane depolarization, overall preventing calcium overload, MPTP opening, and cardiomyocyte death.…”

“…Experimental studies showed promising results as administration of fission proteins inhibitors reduced MI size and improved mitochondrial function in rodents [ 39 ], but more recent data did not confirm such findings and point to possible inhibitor-related mitochondrial damage [ 40 ]. Similarly, results from studies exploring the therapeutic benefits of mitoBK Ca channel activation are on the rise; mitoBK Ca agonists include both synthetic substances (NS1619, NS11021 [ 41 ]) and many endogenous molecules, including nitric oxide, carbon monoxide (CO), and hydrogen sulfide [ 36 ].…”

Multidimensional Regulation of Cardiac Mitochondrial Potassium Channels

“…Cardiac tissue mitochondria contain two potassium channels that can be treated as calcium sensors since they are activated by calcium ions. The first channel belonging to this group was the large-conductance calcium-activated potassium (mitoBK Ca ) channel, which was found in mitochondria of mammalian heart tissue and in cardiac-derived cell lines [ 11 , 38 , 92 , 93 , 94 , 95 ]. These channels are also present in the mitochondria of other tissues such as brain, skeletal muscle, bronchial epithelium or skin fibroblasts [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ].…”

“…BK Ca channels are also present in other organelles [ 101 , 102 , 104 ]. However, it is believed that in cardiomyocytes, BK Ca channels are present exclusively in mitochondria and are not found in the plasma membrane [ 11 , 105 ]. Here, we briefly present key findings that describe cardiac mitoBK Ca channels, and more details are presented in excellent papers [ 11 , 105 , 106 ].…”

“…Despite many open questions about the functioning of these proteins, the molecular identification of the channels has driven intensive pharmacological characterization studies [ 9 , 10 , 11 , 12 , 13 ]. As mentioned above, heart mitochondria contain several types of potassium channels that are regulated by various factors, including ATP (mitoK ATP ), calcium ions (mitoSK Ca , mitoBK Ca ), membrane potential (mitoBK Ca , mitoKv7.4), pH (mitoK ATP ) and ROS and redox-dependent pathways (e.g., mitoK ATP , mitoBK Ca ).…”