Novel role of KCNQ2/3 channels in regulating neuronal cell viability.
Overactivation of certain K(+) channels can mediate excessive K(+) efflux and intracellular K(+) depletion, which are early ionic events in apoptotic cascade. The present investigation examined a possible role of the KCNQ2/3 channel or M-channel (also named Kv7.2/7.3 channels) in the pro-apoptotic process. Whole-cell recordings detected much larger M-currents (212 ± 31 pA or 10.5 ± 1.5 pA/pF) in cultured hippocampal neurons than that in cultured cortical neurons (47 ± 21 pA or 2.4 ± 0.8 pA/pF). KCNQ2/3 channel openers N-ethylmaleimide (NEM) and flupirtine caused dose-dependent K(+) efflux, intracellular K(+) depletion, and cell death in hippocampal cultures, whereas little cell death was induced by NEM in cortical cultures. The NEM-induced cell death was antagonized by co-applied KCNQ channel inhibitor XE991 (10 μM), or by elevated extracellular K(+) concentration. Supporting a mediating role of KCNQ2/3 channels in apoptosis, expression of KCNQ2 or KCNQ2/3 channels in Chinese hamster ovary (CHO) cells initiated caspase-3 activation. Consistently, application of NEM (20 μM, 8 h) in hippocampal cultures similarly caused caspase-3 activation assessed by immunocytochemical staining and western blotting. NEM increased the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), induced mitochondria membrane depolarization, cytochrome c release, formation of apoptosome complex, and apoptosis-inducing factor (AIF) translocation into nuclear. All these events were attenuated by blocking KCNQ2/3 channels. These findings provide novel evidence that KCNQ2/3 channels could be an important regulator in neuronal apoptosis.
Zhou
X
X
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Wei
J
J
Song
M
M
Francis
K
K
Yu
S P
SP
D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053478:Apoptosomes / Q000378:metabolism; D016466:CHO Cells; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D045304:Cytochromes c / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D015640:Ion Channel Gating; D051658:KCNQ2 Potassium Channel / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D021381:Protein Transport
D051033:Apoptosis Inducing Factor; D053478:Apoptosomes; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D045304:Cytochromes c; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3