Agnati L F, Guidolin D, Leo G, Fuxe K
Department of Biomedical Sciences, University of Modena and Reggio Emilia and IRCCS, Ospedale San Camillo, Venezia, Italy.
J Neural Transm (Vienna). 2007 Jan;114(1):77-92. doi: 10.1007/s00702-006-0567-6. Epub 2006 Sep 12.
In the last five years data have been obtained showing that a functional cross-talk among G Protein Coupled receptors (GPCR) exists at the plasma membrane level where they can dimerise and are able to generate high order oligomers. These findings are in agreement with the receptor mosaic (RM) hypothesis that claims the existence of clusters of receptor proteins at the plasma membrane level, where they establish mutual interactions and work as 'intelligent interfaces' between the extra-cellular and the intra-cellular environments. Individual receptor dimers can be considered to have two stable conformational states with respect to the macromolecular effectors: one active, one inactive. Owing to receptor-receptor interactions, however, a state change of a given receptor will change the probability of changing the state for the adjacent receptors in the RM and the effect will propagate throughout the cluster, leading to a complex cooperative behaviour. In this study we explore the properties of a RM on the basis of an equivalence with a Boolean network, a mathematical framework able to describe how complex properties may emerge from systems characterized by deterministic local interactions of many simple components acting in parallel. Computer simulations of receptor clusters arranged according to topologies consistent with available experimental ultrastructural data were performed. They indicated that RMs after a stimulation can achieve a limited number of specific temporary equilibrium configurations (attractors), characterized by the presence of receptor units frozen in the active state. They could be interpreted as a form of information storage and a role of RM in learning and memory could be hypothesized. Moreover, they seem to be at the basis of very common 'macroscopical' properties of a receptor system, such as a sigmoidal response curve to an extracellular ligand, the sensitivity of the mosaic being modulated by changes in the topology and/or in the level of cooperativity among receptors.
在过去五年中，已获得的数据表明，G蛋白偶联受体（GPCR）之间在质膜水平存在功能性相互作用，它们可以二聚化并形成高阶寡聚体。这些发现与受体镶嵌（RM）假说一致，该假说认为在质膜水平存在受体蛋白簇，它们在那里建立相互作用，并作为细胞外和细胞内环境之间的“智能界面”发挥作用。就大分子效应器而言，单个受体二聚体可被认为具有两种稳定的构象状态：一种是活性状态，一种是非活性状态。然而，由于受体 - 受体相互作用，给定受体的状态变化将改变RM中相邻受体状态改变的概率，并且这种效应将在整个簇中传播，导致复杂的协同行为。在本研究中，我们基于与布尔网络的等效性来探索RM的特性，布尔网络是一个数学框架，能够描述复杂特性如何从由许多并行作用的简单组件的确定性局部相互作用所表征的系统中出现。对根据与现有实验超微结构数据一致的拓扑排列的受体簇进行了计算机模拟。结果表明，刺激后的RM可以达到有限数量的特定临时平衡构型（吸引子），其特征是存在处于活性状态的受体单元。它们可以被解释为一种信息存储形式，并且可以假设RM在学习和记忆中发挥作用。此外，它们似乎是受体系统非常常见的“宏观”特性的基础，例如对细胞外配体的S形反应曲线，镶嵌体的敏感性由拓扑结构和/或受体之间的协同水平变化调节。
