The calcium-sensing receptor (CaR) permits Ca2+ to function as a versatile extracellular first messenger

Abstract

The ability of parathyroid cells to recognize and respond to (i.e., "sense") small changes in the extracellular Ca2+ concentration (Ca2+o) plays a crucial role in mineral ion homeostasis. Expression cloning in Xenopus laevis oocytes enabled isolation of a cDNA coding for the bovine parathyroid CaR. CaRs were later isolated from human parathyroid and kidney, rat kidney, brain and C-cell, rabbit kidney, and chicken parathyroid. All are tissue and species homologs of the same ancestral gene. The predicted CaR protein has a large extracellular amino-terminus, which binds polycationic CaR agonists; a central core with seven membrane-spanning helices, documenting that it is a G protein-coupled receptor; and an approximately 200 amino acid carboxyl-terminal tail. The CaR is highly expressed in parathyroid and C-cells, along almost the entire nephron and gastrointestinal (GI) tract and within numerous regions of the brain, particularly hippocampus, cerebellum, and hypothalamus. The CaR's physiological importance has been documented by the identification of hyper- and hypocalcemic syndromes due to inactivating or activating CaR mutations, respectively. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are caused by loss-of-function CaR mutations producing Ca2+o "resistance," while autosomal dominant hypocalcemia is the result of activating mutations rendering CaRs overly sensitive to Ca2+o. In addition to showing altered parathyroid responsiveness to Ca2+o, patients with FHH reabsorb too much urinary Ca2+ and Mg2+ at a given Ca2+o, while those with autosomal dominant hypocalcemia excrete too much, illustrating the CaR's key role in renal handling of divalent cations. Recent in vitro data suggest that the CaR directly regulates renal water handling in the collecting duct. Indeed, patients with FHH concentrate their urine normally, despite their hypercalcemia, while those with autosomal dominant hypocalcemia can exhibit impaired urinary concentration at normal or even low Ca2+o, suggesting that the CaR enables coordination of renal calcium and water handling. In addition to serving these "homeostatic" roles, the CaR likely also enables Ca2+o to serve additional roles as an extracellular messenger. The receptor regulates key Ca2+ and K(+)-permeable ion channels in hippocampal and other brain cells and likely senses local changes in Ca2+o within the brain microenvironment accompanying neuronal activation. It is also present in and regulates ion channels in lens epithelial cells, potentially playing some role in cataract development in hypoparathyroid patients. In keratinocytes and epithelial cells of the gastrointestinal tract, in contrast, the CaR may regulate cellular proliferation and differentiation, processes known to be modulated by Ca2+o in these cell types. Thus, in addition to sensing and regulating systemic Ca2+o, the CaR likely enables Ca2+o to act as a local signal for cells within specific microenvironments, such as the brain or eye.