Intracellular Ca 2+ and cell injury: A paradoxical role of Ca 2+ in complement membrane attack

Abstract

Disturbances in intracellular Ca 2+ are known to be important in cell injury caused by a wide range of toxic factors. The complement system is a major effector of immune damage in vivo, and is known to be involved in the pathogenesis of many immune diseases. We present here evidence that the potentially lethal membrane attack complex of complement causes a rapid increase in intracellular free Ca 2+ concentration before any other detectable biochemical changes in the cell. In nucleated cells the increased intracellular free Ca 2+ concentration initially stimulates recovery processes, allowing the cell to escape mild complement attack and also activates the production of inflammatory mediators, which may amplify an ongoing inflammatory response. More severe complement membrane attack causes a more rapid rise in intracellular free Ca 2+ concentration allowing a threshold to be breached above which recovery processes are overwhelmed, and cell death occurs. The importance of non-lytic effects and recovery processes mediated by Ca 2+, and the molecular basis of these effects are discussed, and the hypothesis proposed that the cell-injuring effects of other “pore-forming” toxins are also caused by increases in intracellular free Ca 2+.