Calcium ion as intracellular messenger and cellular toxin

Ca²⁺ serves a nearly universal intracellular messenger function in cell activation, but excess Ca²⁺ is also a cellular toxin. The possibility of Ca²⁺ intoxication is minimized by an elaborate autoregulatory system in which changes in Ca²⁺ influx rate across the plasma membrane are rapidly compensated for by parallel changes in Ca²⁺ efflux rate. By this mean, cellular Ca²⁺ homestasis is maintained so that minimal changes in total cell calcium and cytosolic Ca²⁺ concentration occur during sustained Ca²⁺-mediated responses. Rather than a sustained increase in cytosolic Ca²⁺ concentration, it is the localized cycling of Ca²⁺ across the plasma membrane that is the critically important Ca²⁺ messenger during the sustained phase of cellular responses mediated via surface receptors linked to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂). PIP₂ hydrolysis gives rise to inositol(1,4,5)trisphosphate (IP₃) and diacylglycerol (DAG). The IP₃ acts to release Ca²⁺ from an intracellular pool, thereby causing a transient rise in cytosolic Ca²⁺ concentration. This transient Ca²⁺ signal activates calmodulin-dependent protein kinases transiently, and hence, causes the transient phosphorylation of a subset of cellular proteins that mediate the initial phase of the response. The DAG brings about the association of protein kinase C (PKC) with the plasma membrane where a receptor-mediated increase in Ca²⁺ cycling across the membrane regulates PKC activity. The sustained phosphorylation of a second subset of proteins by PKC mediates the sustained phase of the response. Hence, Ca²⁺ serves as a messenger during both phases of the cellular response, but its cellular sites of action, its mechanisms of generation, and its molecular targets differ during the initial and sustained phases of the response. It is likely that this Ca²⁺ messenger system is a target for many cellular toxins.