Abstract
The calcium-sensing receptor (CaSR) is a widely expressed homodimeric G-protein coupled receptor structurally related to the metabotropic glutamate receptors and GPRC6A. In addition to its well characterized role in maintaining calcium homeostasis and regulating parathyroid hormone release, evidence has accumulated linking the CaSR with cellular differentiation and migration, brain development, stem cell engraftment, wound healing, and tumor growth and metastasis. Elevated expression of the CaSR in aggressive metastatic tumors has been suggested as a potential novel prognostic marker for predicting metastasis, especially to bone tissue where extracellular calcium concentrations may be sufficiently high to activate the receptor. Recent evidence supports a model whereby CaSR-mediated activation of integrins promotes cellular migration. Integrins are single transmembrane spanning heterodimeric adhesion receptors that mediate cell migration by binding to extracellular matrix proteins. The CaSR has been shown to form signaling complexes with the integrins to facilitate both the movement and differentiation of cells, such as neurons during normal brain development and tumor cells under pathological circumstances. Thus, CaSR/integrin complexes may function as a universal cell migration or homing complex. Manipulation of this complex may be of potential interest for treating metastatic cancers, and for developmental disorders pertaining to aberrant neuronal migration.
Highlights
GENERAL FEATURES OF calcium-sensing receptor (CaSR) STRUCTURE, ACTIVATION, AND EXPRESSIONThe CaSR belongs to the metabotropic glutamate receptor subclass of G-protein coupled receptors (GPCRs)
In addition to amino acids, GPRC6A is activated by testosterone (Ko et al, 2014), and some groups have reported that osteocalcin, a bone-derived peptide that participates in pancreatic beta cell function, is an endogenous ligand (Pi et al, 2011; De Toni et al, 2014; Wei et al, 2014); this remains controversial
CaSR−/− hematopoietic stem cells (HSCs) from fetal liver were normal in number and in proliferative capability, they were highly defective in localizing anatomically to the endosteal niche, a characteristic that correlated with defective adhesion of the HSCs to collagen I, an extracellular matrix protein (ECM) present in the endosteal surface (Adams et al, 2006)
Summary
Hematopoietic stem cells (HSCs) translocate from the fetal liver to the bone marrow where hematopoiesis occurs throughout adulthood. CaSR−/− HSCs from fetal liver were normal in number and in proliferative capability, they were highly defective in localizing anatomically to the endosteal niche, a characteristic that correlated with defective adhesion of the HSCs to collagen I, an extracellular matrix protein (ECM) present in the endosteal surface (Adams et al, 2006). Together, these results indicate that the CaSR is responsible for retaining and adhering HSCs in close physical proximity to the bone endosteal surface. Using this biomaterial, Aguirre et al (2012) demonstrated that bone marrow-derived HSC mobilization, differentiation, and TABLE 1 | Summary of studies linking the CaSR and cellular migration
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