The calcium-sensing receptor and integrins

钙敏感受体（CaSR）是一种G蛋白偶联受体（GPCR），可被阳离子（特别是钙）激活，并协助调节体内钙水平。 它在包括甲状旁腺主细胞和甲状腺C细胞在内的内分泌细胞中高度表达，分别抑制甲状旁腺激素的分泌和促进降钙素的分泌，从而间接调节全身钙代谢的两种相反的调节剂。 然而，最近的研究表明，在中枢神经系统中的神经元过程的生长所需的CaSR。 我们最近发现CaSR与甲状腺癌细胞中称为整联蛋白的一类蛋白质相关，更具体地，CaSR和整联蛋白一起存在于大分子蛋白质复合物中（Tharmalingam et al.，2011年）。 细胞外基质结合蛋白的整合素家族被鉴定为来自CaSR免疫亲和下拉实验的候选CaSR相互作用蛋白。 整合素是一种粘附蛋白，它在细胞内细胞骨架和细胞外环境之间提供功能性连接。 我们发现CaSR的活化促进整合素介导的细胞粘附和向纤连蛋白基质的迁移。 这些令人兴奋的发现首次证明了离子传感GPCR与整合素物理耦合以介导细胞粘附和迁移，并为CaSR和脑发育的研究提供了新的方向。 在这项拨款提案中，我们建议确定这些在甲状腺细胞中的新发现是否延伸到大脑中的神经元和神经胶质细胞。 我们特别感兴趣的是，确定钙调素受体-整合素复合物是否存在于少突胶质细胞（大脑的髓鞘形成细胞）上，如果存在，它是否在髓鞘形成中发挥作用。 我们预计，这项工作将阐明如何增加细胞外钙水平和刺激的CaSR，调节细胞生长，粘附，迁移在中枢神经系统。

The calcium-sensing receptor (CaSR) is a G-protein coupled receptors (GPCR) that is activated by cations, particularly calcium, and assists in the regulation of calcium levels in the body. It is highly expressed in endocrine cells including parathyroid chief cells and thyroid C-cells where it inhibits the secretion of parathyroid hormone and promotes the secretion of calcitonin respectively, thereby reciprocally regulating two opposing regulators of whole body calcium metabolism. However, recent studies have shown that the CaSR is required for the growth of neuronal processes in the central nervous system. We have recently discovered that the CaSR is associated with a class of proteins called the integrins in thyroid carcinoma cells, and more specifically, that the CaSR and integrins are present together in a macromolecular protein complex (Tharmalingam et al., 2011). The integrin family of extracellular matrix binding proteins was identified as candidate CaSR interacting proteins from CaSR immuno-affinity pull-down experiments. Integrins are adhesion proteins that provide the cell with a functional link between the intracellular cytoskeleton and the extracellular environment. We found that the activation of the CaSR promotes integrin mediated cell adhesion and migration towards a fibronectin matrix. These exciting findings demonstrate for the first time that an ion-sensing GPCR physically couples to the integrins to mediate cell adhesion and migration, and provide a new direction for studies on the CaSR and brain development. In this grant proposal, we propose to determine whether these novel findings made in thyroid cells extend to neurons and glial cells in the brain. We are particularly interested in determining if the CaSR-integrin complex is present on oligodendroglia, the myelin forming cells of the brain, and if so, whether it plays a role in myelin formation. We anticipate that this work will shed light on how increased extracellular calcium levels and the stimulation of the CaSR, regulate cell growth, adhesion, migration in the CNS.