ClC-3-independent sensitivity of apoptosis to Cl- channel blockers in mouse cardiomyocytes.
It has been shown that Cl-/HCO3- exchangers and Cl- channels, both of which are sensitive to stilbene derivatives, have essential roles in the mechanism of apoptosis induction. Staurosporine-induced apoptosis in neonatal mouse cardiomyocytes was prevented by a stilbene derivative, DIDS. To clarify whether Cl-/HCO3- exchangers or Cl- channels are targets of DIDS and whether ClC-3 is involved in the apoptotic process, staurosporine-induced reduction of cell viability, DNA laddering and caspase-3 activation were examined in cultured mouse ventricular myocytes derived from wild-type and ClC-3-deficient mice. Staurosporine-induced apoptosis and its DIDS sensitivity in ambient HCO3(-)-free conditions in which operation of Cl-/HCO3- exchangers is minimized were indistinguishable from when HCO3- was present. Apoptosis was also prevented by application of a non-stilbene-derivative Cl- channel blocker, NPPB, which cannot block Cl-/HCO3- exchangers. Cardiomyocytes derived from ClC-3-deficient mice similarly underwent apoptosis after exposure to staurosporine; moreover, apoptosis was prevented by application of DIDS or NPPB. Thus, we conclude that in cardiomyocytes, apoptosis is critically dependent on operation not of Cl-/HCO3- exchangers but of Cl- channels which are distinct from ClC-3.
Takahashi
Nobuyuki
N
Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki, Japan.
Wang
Xiaoming
X
Tanabe
Shigeru
S
Uramoto
Hiromi
H
Jishage
Kouichi
K
Uchida
Shinichi
S
Sasaki
Sei
S
Okada
Yasunobu
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D019311:Staurosporine / Q000494:pharmacology
D018118:Chloride Channels; C115376:ClC-3 channel; D019311:Staurosporine