A Role for BK Channels in Heart Rate Regulation in Rodents

Abstract

The heart generates and propagates action potentials through synchronized activation of ion channels allowing inward Na+ and Ca2+ and outward K+ currents. There are a number of K+ channel types expressed in the heart that play key roles in regulating the cardiac cycle. Large conductance calcium-activated potassium (BK) ion channels are not thought to be directly involved in heart function. Here we present evidence that heart rate can be significantly reduced by inhibiting the activity of BK channels. Agents that specifically inhibit BK channel activity, including paxilline and lolitrem B, slowed heart rate in conscious wild-type mice by 30% and 42%, respectively. Heart rate of BK channel knock-out mice (Kcnma1−/−) was not affected by these BK channel inhibitors, suggesting that the changes to heart rate were specifically mediated through BK channels. The possibility that these effects were mediated through BK channels peripheral to the heart was ruled out with experiments using isolated, perfused rat hearts, which showed a significant reduction in heart rate when treated with the BK channel inhibitors paxilline (1 µM), lolitrem B (1 µM), and iberiotoxin (0.23 µM), of 34%, 60%, and 42%, respectively. Furthermore, paxilline was shown to decrease heart rate in a dose-dependent manner. These results implicate BK channels located in the heart to be directly involved in the regulation of heart rate.

Targeted next-generation sequencing detects point mutations, insertions, deletions and balanced chromosomal rearrangements as well as identifies novel leukemia-specific fusion genes in a single procedure

“…This gene, a potassium large conductance calcium-activated channel family member on chromosome 10q22.3, has been reported to be fundamental to the control of smooth muscle tone and neuronal excitability. [31][32][33] In our patient the RUNX1-KCNMA1 fusion, as confirmed by RT-PCR and Sanger sequencing, led to the disruption of the 'Runt homology domain' (RHD) of RUNX1 (Figure 4b). The break point in RUNX1 was detected in intron 3-4 (ENST00000300305), whereas in t(8;21) the genomic break point is located in intron 5, after the RHD domain.…”

Sympathetic nerve stimulation induces local endothelial Ca2+ signals to oppose vasoconstriction of mouse mesenteric arteries

“…IK channels were blocked using the synthetic inhibitor Tram-34 and the scorpion toxin charybdotoxin (ChTx), which also blocks large-conductance (BK) Ca 2ϩ -sensitive K ϩ channels, but not SK channels, with high affinity (3,28). In experiments using ChTx, the potential effects of BK channels, which are expressed in VSMCs but not in normal ECs (8,20,26,34), were eliminated using the selective blocker paxilline (13,28,29). Elevation of intravascular pressure to 80 mmHg induced myogenic tone, constricting these mesenteric arteries by 22.7 Ϯ 0.8% (n ϭ 34).…”

SK4 Ca 2+ activated K + channel is a critical player in cardiac pacemaker derived from human embryonic stem cells

“…Large-conductance Ca 2+ -activated big conductance Ca 2+ -activated (BK Ca ) K + channels are not expressed in the sarcolemma of cardiomyocytes (37). However, a recent report suggested that BK Ca channels could play a role in heart rate regulation (38). Thus, we examined the effects of iberiotoxin (100 nM), a selective inhibitor of BK Ca channels, on the pacing of hESC-CMs.…”