title: Window current through the T-type Ca2+ channel triggers the mechanism for cellular apoptosis via mitochondrial pathways.
abstract: We hypothesized that Ca(2+) entry through the window T-type Ca(2+) current causes apoptosis. To test this hypothesis, we transfected human embryonic kidney (HEK) 293 cells to express recombinant Cav3.2 T-type Ca(2+) channels (hereafter called HEK-Cav3.2 cells). After incubation in media containing a high concentration (7.2 mM) of Ca(2+), intracellular Ca(2+) levels increased in HEK-Cav3.2 cells without electrical stimulation but not in untransfected HEK293 cells. In quiescent HEK-Cav3.2 cells exposed to high Ca(2+) media, apoptosis, as indicated by the appearance of hypodiploid cells, loss of mitochondrial transmembrane potential, and activation of caspases-3 and -9 was observed, while caspase-8 was not activated. These apoptosis-associated changes were blunted by pretreatment with the R(-)-isomer of efonidipine, a selective blocker of T-type Ca(2+) channels. High Ca(2+) did not induce apoptosis in untransfected HEK293 cells. Our findings show that Ca(2+) entry through the steady-state window current of T-type Ca(2+) channels causes apoptosis via mitochondrial pathways, and suggests that T-type Ca(2+) channels may be novel therapeutic targets for several diseases associated with abnormal apoptosis.
authors: Department of Pathophysiology, Oita University School of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan.
authors: Tomoko
authors: T
authors: Uchino
authors: Shojiro
authors: S
authors: Isomoto
authors: Takayuki
authors: T
authors: Noguchi
authors: Katsushige
authors: K
authors: Ono
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D053078:Membrane Potential, Mitochondrial; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9