Trends in Pharmacological Sciences
Role of Ca2+ in toxic cell killing
Abstract
Recent work has shown that a sustained increase in cytosolic Ca2+ concentration is often linked to the onset of cytotoxicity. Sten Orrenius and colleagues describe several biochemical mechanisms that are stimulated by such a Ca2+ increase and can directly mediate cell death by causing disruption of the cytoskeleton, DNA fragmentation and extensive damage to other cell components.
References (34)
- H. Komulainen et al.
Trends Pharmacol. Sci.
(1988) - P. Nicotera et al.
Toxicology
(1988) - F.J.G.M. Van Kuijk et al.
Trends Biochem. Sci.
(1987) - E.A. Glende et al.
Biochem. Pharmacol.
(1986) - T. Murachi et al.
Adv. Enzyme Regul.
(1981) - P. Nicotera
J. Biol. Chem.
(1986) - D.J. McConkey
Arch. Biochem. Biophys.
(1989) - D.P. Jones et al.
J. Biol. Chem.
(1989) - D.J. McConkey et al.
Toxicol. Lett.
(1988) - P. Waring et al.
J. Biol. Chem.
(1988)
Am. J. Pathol.
Science
Science
EMBO J.
FASEB J.
Biochem. Pharmacol.
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