The mitochondrial ADPR link between Ca2+ store release and Ca2+ influx channel opening in immune cells

The regulation of non-voltage-operated Ca2+ channels in the plasma membrane remains unclear (1-3). However, there is often a link between the physiological release of Ca2+ from intracellular stores and opening of Ca2+ influx channels on the plasma membrane. This route has been referred to variously as store-operated Ca2+ entry (SOC), capacitative Ca2+ entry, and Ca2+ release-activated channel opening (CRAC), and often underlies the large changes in cytosolic free Ca2+ that accompany many stimuli in a wide variety of cell types (1-3). The linkage between Ca2+ store release and opening of Ca2+ channels on the plasma membrane has remained elusive for a number of years, perhaps in part because different mechanisms exist for this linkage, and are used to differing extents by different cells. We suggest here that one of the mechanisms that may operate in cells of the immune system, but that may be important elsewhere, involves the release of mitochondrial adenosine diphosphate ribose (ADPR) or nicotinamide adenine dinucleotide (NAD(+)). There is accumulating evidence to support each of the steps necessary for a complete description of this "Ca2+ store release to plasma membrane channel opening" link, but to our knowledge they have not been connected before to make a coherent model.