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.
Highlights
In the early 1980s, ‘big K’ channel (BKCa ), named after its large single-channel conductance250–300 pS, was originally cloned in Drosophila at the slowpoke [1,2].In mammals, BKCa channels were defined as large-conductance calcium-activated potassium ion channels (BKCa, MaxiK, KCa 1.1, Slo1) and were characterized in bovine chromaffin cells, rabbit skeletal muscle, and rat muscle cells [1,2,3]
BKCa in sinoatrial node (SAN) are shown to be functionally coupled with L-type calcium channel Cav 1.3, which are expressed in sinoatrial and atrioventricular nodes but not in ventricular cardiomyocytes, and are responsible for pacemaker currents [59]
There are conflicting data showing contradictory results that vary from inhibition of native and recombinant currents of the α subunit expressed in human embryonic kidney (HEK)-293 cells [101], through to β1 subunit presence and enhanced oxidative regulation and BKCa activation [102], to the BKCa response dependent on channel priming by PKG phosphorylation [103]
Summary
In the early 1980s, ‘big K’ channel (BKCa ), named after its large single-channel conductance. Kcnma gene codes for α-subunit that assembles into a pore-forming tetramer, a primary BKCa channel functional unit [23]. Though BKCa channels are uniformly present in all cell types, they have recently been brought into the forefront in cardiovascular studies [4,10,28,29,30,31,32,33,34] They have been implicated in several pathophysiological conditions and cardiovascular diseases [2,5,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51]. We exclusively focus on the functions of BKCa channels in the cardiac system and their role in protection from acute myocardial infarction (AMI)
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