Cytochrome c activates K+ channels before inducing apoptosis

Cellshrinkage is an early prerequisite for apoptosis. Theapoptotic volume decrease is due primarily to loss ofcytoplasmic ions. Increased outward K⁺ currents have indeedbeen implicated in the early stage of apoptosis in many celltypes. We found that cytoplasmic dialysis of cytochrome c(cyt-c), a mitochondria-dependent apoptotic inducer,increases K⁺ currents before inducing nuclear condensationand breakage in pulmonary vascular smooth muscle cells. Thecyt-c-mediated increase in K⁺ currents tookplace rapidly and was not affected by treatment with a specificinhibitor of caspase-9. Cytoplasmic dialysis of recombinant (active)caspase-9 negligibly affected the K⁺ currents. Furthermore,treatment of the cells with staurosporine (ST), an apoptosisinducer that mediates translocation of cyt-c frommitochondria to the cytosol, also increased K⁺ currents,caused cell shrinkage, and induced apoptosis (determined byapoptotic nuclear morphology and TdT-UTP nick end labeling assay).The staurosporine-induced increase in K⁺ currents concurredto the volume decrease but preceded the activation of apoptosis(nuclear condensation and breakage). These results suggest that thecyt-c-induced activation of K⁺ channels and theresultant K⁺ loss play an important role in initiating theapoptotic volume decrease when cells undergo apoptosis.