G Protein-Coupled Extracellular Ca2+ (Ca2+oRpar;–Sensing Receptor (CaR): Roles in Cell Signaling and Control of Diverse Cellular Functions

Abstract

Publisher Summary A body of indirect evidence had suggested the presence of a Ca 2+ o -sensing mechanism in parathyroid cells, C-cells, and kidney cells, through which Ca 2+ o could act, in effect, as an extracellular first messenger via its own putative G protein-coupled, cell surface receptor. Such evidence, principally accumulated in studies, involving dispersed bovine parathyroid cells, included some well-defined actions of the elevated Ca 2+ o . The body of evidence, suggesting the existence of a Ca 2+ o -sensing receptor, provides a foundation for the successful use of expression cloning in Xenopm laevis oocytes to isolate a full-length complementary DNA (cDNA), encoding the bovine parathyroid Ca 2+ o -sensing receptor (abbreviated as CaR). Research shows that the CaR provide the molecular basis for a number of the known effects of Ca 2+ o on its target tissues involved in mineral ion homeostasis, especially parathyroid and kidney. Although additional studies are needed to prove its mediatory role, the CaR may likewise participate in the aspects of the control of intestinal function and bone turnover that are relevant to systemic mineral ion metabolism. This receptor also plays key roles in human disorders, such as familial hypocalciuric hypercalcemia (FHH)/neonatal severe hyperparathyroidism (NSHPT), autosomal dominant hypocalcemia, and sporadic hypocalcemia/hypoparathyroidism as well as in the impaired urinary concentrating capacity or, in some cases, frank nephrogenic diabetes insipidus observed in hypercalcemic persons. However, findings of the wide distribution of the CaR in tissues uninvolved in systemic Ca 2+ o homeostasis indicate that the CaR also participates in modulating the neuronal activities in the brain and perhaps intestine as well as a variety of other cellular functions.