The dual role of calcium as messenger and stressor in cell damage, death, and survival

Abstract

Ca(2+) is an important second messenger participating in many cellular activities; when physicochemical insults deregulate its delicate homeostasis, it acts as an intrinsic stressor, producing/increasing cell damage. Damage elicits both repair and death responses; intriguingly, in those responses Ca(2+) also participates as second messenger. This delineates a dual role for Ca(2+) in cell stress, making difficult to separate the different and multiple mechanisms required for Ca(2+)-mediated control of cell survival and apoptosis. Here we attempt to disentangle the two scenarios, examining on the one side, the events implicated in deregulated Ca(2+) toxicity and the mechanisms through which this elicits reparative or death pathways; on the other, reviewing the role of Ca(2+) as a messenger in the transduction of these same signaling events.

Figure 1

Ca²⁺ signals between ER and mitochondria coordinate the precommitment phase of apoptosis: amplification loops between Bax activation and Ca²⁺ release from ER amplify cytochrome c release to a level sufficient for apoptosome nucleation and caspase activation. Cytochrome c released by Bax (1) or VDAC (2) mitochondrial pores magnifies Ca²⁺ efflux from IP₃ channels; the consequent local high cytosolic Ca²⁺ recruits Bax (via calpain?) to mitochondria or ER membrane, stimulating more cytochrome c release and more Ca²⁺ efflux, respectively.

Figure 2

Capacitative and noncapacitative Ca²⁺ entry. Ligand (L) stimulation of G-protein (α β γ)-coupled receptor (R) activates phospholipase C (PLC) to produce diacylglycerol (DAG) and inositol-3-phosphate (IP₃). IP₃ (right side) causes ER Ca²⁺ emptying, eliciting a capacitative Ca²⁺ entry (CCE) through plasma membrane (PM), aimed at refilling ER of Ca²⁺ restoring ER homeostasis. DAG (left side) is processed to arachidonic acid (AA) by DAG lipase (DAGL), stimulating NOS to produce NO, which activates Ca²⁺ entry through PM by a noncapacitative Ca²⁺ entry (NCCE), priming specific signaling including anti-apoptotic pathways. CCE and NCCE differ in protein composition [124]. Red dots symbolize Ca²⁺.

Figure 3

Temporary ER Ca²⁺ anergy avoid loss of repairable cells. Cell damage elicits repair and apoptosis as well as standby periods (red arrows). ER Ca²⁺ anergy is temporarily achieved via ADP-ribosylation of GAPDH, glycolysis block and starvation of Ca²⁺-ATPases, and hampers apoptotic signal transduction at the ER signaling stage. After resumption of glycolysis and ER Ca²⁺ activity, the apoptotic signal is allowed to proceed, unless successful repair has occurred in the meantime.

Figure 4

Ca²⁺ signaling in survival and apoptosis versus deregulation of Ca²⁺ homeostasis as necrogenic event.