Advances in Experimental Medicine and Biology vol:740 pages:255-279
Activation of cells by many extracellular agonists leads to the production of inositol 1,4,5-trisphosphate (IP(3)). IP(3) is a global messenger that easily diffuses in the cytosol. Its receptor (IP(3)R) is a Ca(2+)-release channel located on intracellular membranes, especially the endoplasmic reticulum (ER). The IP(3)R has an affinity for IP(3) in the low nanomolar range. A prime regulator of the IP(3)R is the Ca(2+) ion itself. Cytosolic Ca(2+) is considered as a co-agonist of the IP(3)R, as it strongly increases IP(3)R activity at concentrations up to about 300 nM. In contrast, at higher concentrations, cytosolic Ca(2+) inhibits the IP(3)R. Also the luminal Ca(2+) sensitizes the IP(3)R. In higher organisms three genes encode for an IP(3)R and additional diversity exists as a result of alternative splicing mechanisms and the formation of homo- and heterotetramers. The various IP(3)R isoforms have a similar structure and a similar function, but due to differences in their affinity for IP(3), their variable sensitivity to regulatory parameters, their differential interaction with associated proteins, and the variation in their subcellular localization, they participate differently in the formation of intracellular Ca(2+) signals and this affects therefore the physiological consequences of these signals.