Calcium mobilization by inositol phosphates and other intracellular messengers

Inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] is now widely recognized as a messenger controlling the release of calcium from intracellular stores. In oocytes, and also probably in excitable cells, another potential calcium-mobilizing messenger is cyclic ADP ribose, although there is as yet little evidence that its levels are regulated by hormones or other extracellular mediators. In addition to signaling intracellular calcium release, [Ins(1,4,5)P(3)] also regulates calcium entry across the plasma membrane, but not in a direct manner. Rather, the depletion of intracellular stores by the calcium-mobilizing action of [Ins (1,4,5)P(3)] initiates a process of retrograde signaling whereby the depleted stores generate or release a diffusible messenger that is believed to act on the plasma membrane. A phosphorylated metabolite of [Ins(1,4,5)P(3)], inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)], has been proposed to modulate this process, but the literature is not consistent on this point. A recently proposed candidate for the retrograde messenger is an activity extracted from Jurkat cells termed CIF (calcium influx factor), which has many properties consistent with such a messenger. There is also evidence that a GTP-dependent process, possibly involving a small G protein, is involved in signaling calcium entry and may be involved in either the formation or action of the diffusible messenger for calcium entry.