De Smedt H, Parys J B
Laboratorium voor Fysiologie, Campus Gasthuisberg O/N-Katholieke Universiteit Leuven.
Verh K Acad Geneeskd Belg. 1995;57(5):423-58.
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.
人们观察到细胞内钙离子作用存在显著的双重性。一方面，钙离子是一种通用的第二信使，另一方面，钙离子浓度的持续升高会导致病理状况。这就是钙离子信号以复杂的时空模式出现，如波和振荡的原因。这种行为反映了在调节钙离子波动的分子和功能参数水平上存在基本的异质性。复杂钙离子信号的分子基础是负责从细胞内储存库释放钙离子的肌醇三磷酸受体（InsP3R）的再生特性。在这项工作中，我们描述了不同细胞类型中InsP3R亚型表达的定性和定量分析。结果表明，至少存在5种不同的亚型，其中II型、IV型以及新描述的V型受体形成一个亚家族。I型受体普遍存在，但大多数细胞类型还会额外表达一种或多种亚型。在这项工作的第二部分，我们描述了InsP3R与InsP3以及变构因子相互作用导致的功能异质性。在本研究中，我们证明InsP3R亚型对InsP3的敏感性存在显著差异。InsP3R的一个极其重要的调节因子是钙离子本身。胞质钙离子具有刺激和抑制作用。储存库腔内的钙离子也是InsP3R的重要调节因子。在这项工作的第三部分，我们将观察到的分子和功能异质性与复杂钙离子信号的基本生理特性，如量子释放、钙离子振荡和钙离子波进行了关联。InsP3R的亚型多样性以及胞质和腔内钙离子对其的调节对于钙离子信号的精细调节都是必要的。亚型多样性也可能在极化细胞中存在的不对称信号的起源以及通过质膜和核周膜的InsP3依赖性信号中发挥作用。
