mitoBK _Ca is encoded by the Kcnma1 gene, and a splicing sequence defines its mitochondrial location

Abstract

The large-conductance Ca 2+ - and voltage-activated K + channel (BK Ca, MaxiK), which is encoded by the Kcnma1 gene, is generally expressed at the plasma membrane of excitable and nonexcitable cells. However, in adult cardiomyocytes, a BK Ca -like channel activity has been reported in the mitochondria but not at the plasma membrane. The putative opening of this channel with the BK Ca agonist, NS1619, protects the heart from ischemic insult. However, the molecular origin of mitochondrial BK Ca (mitoBK Ca ) is unknown because its linkage to Kcnma1 has been questioned on biochemical and molecular grounds. Here, we unequivocally demonstrate that the molecular correlate of mitoBK Ca is the Kcnma1 gene, which produces a protein that migrates at ∼140 kDa and arranges in clusters of ∼50 nm in purified mitochondria. Physiological experiments further support the origin of mitoBK Ca as a Kcnma1 product because NS1619-mediated cardioprotection was absent in Kcnma1 knockout mice. Finally, BK Ca transcript analysis and expression in adult cardiomyocytes led to the discovery of a 50-aa C-terminal splice insert as essential for the mitochondrial targeting of mitoBK Ca .

Ca²⁺-Activated K⁺ Channels as Therapeutic Targets for Myocardial and Vascular Protection

“…In addition, Singh et al recently demonstrated that cardiomyocyte BKCa channels contain a novel C-terminal splice variant (termed DEC), which when expressed localizes the channel exclusively to cardiomyocyte mitochondria. 7 Importantly, there is no known expression of BKCa channels on the cardiomyocyte plasma membrane. Activation of plasma membrane K + currents could lead to altered action potential and arrhythmia, as seen with KATP modulating compounds.…”

“…40 In addition, Singh et al showed that mitochondria treated with NS1619 had increased resistance to Ca 2+ -induced MPTP opening. 7 Interestingly, both the BKCa activators, NS11021 and NS1619, elicit minor if any detectable depolarization of mitochondrial membrane potential when used at appropriate BKCa-activating concentrations. 15, 41 Therefore, charge-mediated limitations of Ca 2+ influx would likely be equally mild.…”

“…3,7,8 Mitochondrial BKCa channel expression has been controversial, presumably because of the low levels of expression and less than optimal available antibodies. BKCa-like currents in mitochondria were first described by Xu et al, who also showed significant cardioprotection using the BKCa activator NS1619 in guinea pig hearts.…”

Designing a capacitated multi-configuration logistics network under disturbances and parameter uncertainty: a real-world case of a drug supply chain

“…Moreover, Ben-Tal et al (2009) modeled the multi-term inventory control problem conducive to optimize the expected cost that includes the costs of flows, transfer links, capacities, and middle-stage facility locations. Singh et al (2013) formulated a two-phase stochastic programming formulation for capacitated network design of an SC with flexible demands. Bayati et al (2013) proposed an optimal pricing and marketing planning where the primary objective function is to maximize the total profit.…”

BKCa channel activation increases cardiac contractile recovery following hypothermic ischemia/reperfusion

“…More recently, the Ca 2ϩ -activated large-conductance K ϩ (BKCa) channel has also been recognized as having potent cardioprotective properties. BKCa activation reduces myocardial infarction, promotes survival, and improves cardiac and vascular function following severe ischemic insults (3,7,9,12,31,32,34,36). In addition, BKCa channels may be more potently cardioprotective than mitoK ATP channels (17).…”