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Abstract
The discovery of a G protein–coupled, calcium-sensing receptor (CaR) a decade ago and of diseases caused by CaR mutations provided unquestionable evidence of the CaR's critical role in the maintenance of systemic calcium homeostasis. On the cell membrane of the chief cells of the parathyroid glands, the CaR “senses” the extracellular calcium concentration and, subsequently, alters the release of parathyroid hormone (PTH). The CaR is likewise functionally expressed in bone, kidney, and gut—the three major calcium-translocating organs involved in calcium homeostasis. Intracellular signal pathways to which the CaR couples via its associated G proteins include phospholipase C (PLC), protein kinase B (AKT); and mitogen-activated protein kinases (MAPKs). The receptor is widely expressed in various tissues and regulates important cellular functions in addition to its role in maintaining systemic calcium homeostasis, i.e., protection against apoptosis, cellular proliferation, and membrane voltage. Functionally significant mutations in the receptor have been shown to induce diseases of calcium homeostasis owing to changes in the set point for calcium-regulated PTH release as well as alterations in the renal handling of calcium. Gain-of-function mutations cause hypocalcemia, whereas loss-of-function mutations produce hypercalcemia. Recent studies have shown that the latter clinical presentation can also be caused by inactivating autoantibodies directed against the CaR. Newly discovered type II allosteric activators of the CaR have been found to be effective as a medical treatment for renal secondary hyperparathyroidism.
| Abbreviations | ||
| ACTH | = | adrenocorticotropic hormone |
| ADH | = | autosomal dominant hypoparathyroidism |
| AH | = | acquired hypoparathyroidism |
| AKT | = | protein kinase B |
| AMG 073 | = | calcimimetic |
| AQP | = | aquaporin |
| BMD | = | bone mineral density |
| BRET | = | bioluminescense resonance energy transfer technique |
| Ca | = | calcium |
| Ca2+i | = | intracellular calcium |
| Ca2+o | = | extracellular calcium |
| cAMP | = | cyclic AMP |
| CaR | = | calcium-sensing receptor |
| CT | = | calcitonin |
| cTAL | = | cortical thick ascending limb of Henle's loop |
| CNS | = | central nervous system |
| Cr | = | creatinine |
| ECD | = | extracellular domain |
| ERK1/2 | = | extracellular signal–regulated kinases 1 and 2 |
| FHH | = | familial hypocalciuric hypercalcemia |
| GABA | = | gamma-aminobutyric acid |
| GPCR | = | G protein-coupled receptor |
| HEK | = | human embryonic kidney |
| HHM | = | humoral hypercalcemia of malignancy |
| HPT | = | hyperparathyroidism |
| ICD | = | intracellular domain |
| IMCD | = | inner medullary collecting duct |
| IP3 | = | inositol trisphosphate |
| MAPK | = | mitogen-activated protein kinase |
| mTAL | = | medullary thick ascending limb |
| NSHPT | = | neonatal severe primary hyperparathyroidism |
| OMIM | = | on-line Mendelian Inheritance in Man |
| PHPT | = | primary hyperparathyroidism |
| PI3K | = | phosphatidylinositol 3-kinase |
| PK | = | protein kinase |
| PL | = | phospholipase |
| PTH | = | parathyroid hormone |
| PTHrP | = | parathyroid hormone–related peptide |
| SNP | = | single nucleotide polymorphism |
| TAL | = | thick ascending limb of Henle's loop |
| TMD | = | transmembrane domain |
| Vitamin D | = | 1,25(OH)2 vitamin D3. |
| Abbreviations | ||
| ACTH | = | adrenocorticotropic hormone |
| ADH | = | autosomal dominant hypoparathyroidism |
| AH | = | acquired hypoparathyroidism |
| AKT | = | protein kinase B |
| AMG 073 | = | calcimimetic |
| AQP | = | aquaporin |
| BMD | = | bone mineral density |
| BRET | = | bioluminescense resonance energy transfer technique |
| Ca | = | calcium |
| Ca2+i | = | intracellular calcium |
| Ca2+o | = | extracellular calcium |
| cAMP | = | cyclic AMP |
| CaR | = | calcium-sensing receptor |
| CT | = | calcitonin |
| cTAL | = | cortical thick ascending limb of Henle's loop |
| CNS | = | central nervous system |
| Cr | = | creatinine |
| ECD | = | extracellular domain |
| ERK1/2 | = | extracellular signal–regulated kinases 1 and 2 |
| FHH | = | familial hypocalciuric hypercalcemia |
| GABA | = | gamma-aminobutyric acid |
| GPCR | = | G protein-coupled receptor |
| HEK | = | human embryonic kidney |
| HHM | = | humoral hypercalcemia of malignancy |
| HPT | = | hyperparathyroidism |
| ICD | = | intracellular domain |
| IMCD | = | inner medullary collecting duct |
| IP3 | = | inositol trisphosphate |
| MAPK | = | mitogen-activated protein kinase |
| mTAL | = | medullary thick ascending limb |
| NSHPT | = | neonatal severe primary hyperparathyroidism |
| OMIM | = | on-line Mendelian Inheritance in Man |
| PHPT | = | primary hyperparathyroidism |
| PI3K | = | phosphatidylinositol 3-kinase |
| PK | = | protein kinase |
| PL | = | phospholipase |
| PTH | = | parathyroid hormone |
| PTHrP | = | parathyroid hormone–related peptide |
| SNP | = | single nucleotide polymorphism |
| TAL | = | thick ascending limb of Henle's loop |
| TMD | = | transmembrane domain |
| Vitamin D | = | 1,25(OH)2 vitamin D3. |