[Molecular and functional diversity of inositol triphosphate-induced Ca(2+) release]

A remarkable duality concerning the role of intracellular Ca2+ ions is observed. At one side Ca2+ is a universal secondary messenger, and at the other side a prolonged increase of the Ca2+ concentration will lead to pathological conditions. This is the reason that Ca2+ signals occur in complex spatio-temporal patterns such as waves and oscillations. This behaviour reflects the existence of a fundamental heterogeneity at the level of the molecular and functional parameters that regulate the Ca2+ fluctuations. The molecular basis of the complex Ca2+ signals is the regenerative character of the inositol trisphosphate receptor (InsP3R) responsible for the release of Ca2+ from intracellular stores. In this work, we describe the qualitative and quantitative analysis of the expression of the InsP3R isoforms in various cell types. It appeared that there exist at least 5 different isoforms and that the isoforms of type II, IV and the newly described receptor of type V form a sub-family. The type I receptors are ubiquitous, but most cell types express in addition one or more isoforms. In the second part of this work, we describe the functional heterogeneity that results from the interaction of the InsP3R with InsP3 as well as with allosteric factors. In this study we demonstrate that the InsP3R isoforms show remarkable differences with respect to their sensitivity for InsP3. An extremely important modulator of the InsP3R is the Ca2+ ion itself. Cytosolic Ca2+ has a stimulatory as well as an inhibitory role. The Ca2+ present in the lumen of the store is also an important regulator of the InsP3R. In the third part of this work we have made a correlation between the observed molecular and functional heterogeneity and the fundamental physiological properties of complex Ca2+ signals, like quantal release, Ca2+ oscillations and Ca2+ waves. Both the isoform diversity and the regulation of the InsP3R by cytosolic and luminal Ca2+ are necessary for the fine-tuning of the Ca2+ signals. The isoform diversity may also play a role in the origin of asymmetrical signals present in polarised cells and in the InsP3-dependent signals through the plasma membrane and through the perinuclear membrane.