Neuronal Ca2+-Activated K+ Channels Limit Brain Infarction and Promote Survival

Abstract

Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca2+ ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by selective BK-channel manipulations in vivo. To elucidate the in vivo contribution of neuronal BK channels in acute focal cerebral ischemia, we performed middle cerebral artery occlusion (MCAO) in mice lacking BK channels (homozygous mice lacking the BK channel alpha subunit, BK−/−). MCAO was performed in BK−/− and WT mice for 90 minutes followed by a 7-hour-reperfusion period. Coronal 1 mm thick sections were stained with 2,3,5-triphenyltetrazolium chloride to reveal the infarction area. We found that transient focal cerebral ischemia by MCAO produced larger infarct volume, more severe neurological deficits, and higher post-ischemic mortality in BK−/− mice compared to WT littermates. However, the regional cerebral blood flow was not significantly different between genotypes as measured by Laser Doppler (LD) flowmetry pre-ischemically, intra-ischemically, and post-ischemically, suggesting that the different impact of MCAO in BK−/− vs. WT was not due to vascular BK channels. Furthermore, when NMDA was injected intracerebrally in non-ischemic mice, NMDA-induced neurotoxicity was found to be larger in BK−/− mice compared to WT. Whole-cell patch clamp recordings from CA1 pyramidal cells in organotypic hippocampal slice cultures revealed that BK channels contribute to rapid action potential repolarization, as previously found in acute slices. When these cultures were exposed to ischemia-like conditions this induced significantly more neuronal death in BK−/− than in WT cultures. These results indicate that neuronal BK channels are important for protection against ischemic brain damage.

Critical role of large-conductance calcium- and voltage-activated potassium channels in leptin-induced neuroprotection of N-methyl-d-aspartate-exposed cortical neurons

“…These results suggest that BK channels, though involved in leptin-induced protection, do not mediate NMDA-induced damage. By contrast, Liao et al (2010) showed greater neurotoxicity by intra-cerebral injection of NMDA in Slo 1 −/− mice when compared to Slo 1 +/+ mice; however, it should be emphasized that, in our in vitro model, the extracellular concentrations of endogenous glutamate are unlikely to achieve the high neurotoxic levels observed in the intact tissue in vivo during NMDA-induced neurodegeneration.…”

Characteristics of single large-conductance Ca2+-activated K+ channels and their regulation of action potentials and excitability in parasympathetic cardiac motoneurons in the nucleus ambiguus

“…Liao et al (35) showed middle cerebral artery occlusion in mice lacking BK channels (loss-offunction) produced a significantly larger infarct volume and led to more severe neurological deficits and higher postischemic mortality than control wild type mice. Previously, we have demonstrated that PCMNs in the NA play a key role in regulating cardiac functions and that chronic intermittent hypoxia (CIH; a model for sleep apnea) may reduce PCMN control over the heart rate and induce cell loss (8,9,72,73,74).…”

“…These negative feedback mechanisms allow BK channels to play key roles in regulating firing properties, such as repetitive firing of neurons (67), spike broadening during repetitive firing (59), and spikefrequency adaptation (26). There has also been evidence that BK channels can moderate neurotransmitter release and provide some protection against neuronal death (35,51,52,68).…”

Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells

“…From studies in macrophages, neutrophils, and mast cells, we learned that changes in the cell membrane potential commonly precede secretory events (21,30), but the mechanisms regulating inflammatory cytokine secretion from AECs remain poorly understood. As in many biological systems, opening of Ca 2ϩ channels is thought to cause membrane depolarization and mediator secretion (35,57), whereas opening of K ϩ channels is generally associated with membrane repolarization and stabilization of the resting membrane potential (29,40). A relatively new family of K ϩ channels, two-pore-domain K ϩ (K2P) channels, are strong candidates as important regulators of the cell membrane potential (4).…”