The calcium-sensing receptor and integrins

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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.