| Summary: | The large-conductance calcium- and voltage-activated K<sup>+</sup> channel (BK<sub>Ca</sub>) are encoded by the <i>Kcnma1</i> 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<sub>Ca</sub> is known to localize to mitochondria. BK<sub>Ca</sub> 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<sub>Ca</sub> 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<sub>Ca</sub> 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<sub>Ca</sub> channels and cardioprotection and explore their potential roles as therapeutic targets for preventing acute myocardial infarction.
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