Inositol trisphosphate and calcium mobilization

Calcium-mobilizing agonists act by stimulating the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P2) to inositol 1,4,5-trisphosphate and diacylglycerol (DG). In response to such agonists cells also produce inositol 1,3,4-trisphosphate but this isomer is unlikely to influence calcium mobilization. Application of inositol 1,4,5-trisphosphate (Ins1,4,5P3) to permeabilized cells results in a rapid release of calcium from the endoplasmic reticulum. Structure-activity studies reveal that the vicinal phosphates on the 4- and 5-positions are essential for releasing calcium whereas the phosphate on the opposite side enhances the affinity of Ins1,4,5P3 for its putative receptor. The flow of calcium across the endoplasmic reticulum appears to be electrogenic and requires an opposite flow of potassium to neutralize charge movements. Diacylglycerol, acting through protein kinase C, does not play a direct role in calcium signalling but it does modulate various aspects of the InsP3/Ca2+ pathway. The DG/protein kinase C pathway can influence both the formation and hydrolysis of PtdIns4,5P2 and can alter the responsiveness of various processes to the action of calcium. The Ins1,4,5P3/Ca2+ signal pathway functions throughout the life history of cells to regulate such diverse activities as egg maturation and fertilization, growth, secretion, metabolism, neural activity, and perhaps excitation-contraction coupling in skeletal muscle.