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Activating mutations of the Ca2+-sensing receptor
E E Mancilla1, F De Luca, J Baron
1National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
The Ca2+-sensing receptor (CaR) is a member of the seven-transmembrane domain, G-protein-coupled receptor superfamily. It is expressed in parathyroid, kidney, and other tissues. In parathyroid, activation of the CaR by extracellular Ca2+ negatively regulates the secretion of parathyroid hormone. In the the thick ascending limb of Henle's loop, receptor activation decreases renal reabsorption of Ca2+. Heterozygous inactivating mutations of the CaR cause familial benign hypocalciuric hypercalcemia while homozygous inactivating mutations cause neonatal severe hyperparathyroidism. Conversely, activating mutations of the CaR cause autosomal dominant and sporadic hypoparathyroidism. Affected individuals have hypocalcemia which ranges from mild and asymptomatic to life-threatening. They also show a greater tendency to hypercalciuria than do other patients with hypoparathyroidism. Most, but not all, of the reported activating mutations occur in the amino-terminal, extracellular domain of the receptor. When expressed in cultured cells, mutant receptors can show both increased receptor sensitivity to Ca2+ and increased maximal signal transduction capacity.
Insights
Mutations in the calcium-sensing receptor (CaR) disrupt calcium homeostasis. Activating CaR mutations cause hypoparathyroidism with hypercalciuria, while inactivating mutations lead to hypercalcemia.
Area of Science:
- Endocrinology
- Molecular Biology
- Nephrology
Background:
- The calcium-sensing receptor (CaR), a G-protein-coupled receptor, regulates calcium homeostasis.
- CaR is expressed in the parathyroid glands and kidneys, influencing parathyroid hormone secretion and calcium reabsorption.
- Dysregulation of CaR function is implicated in various human disorders.
Purpose of the Study:
- To elucidate the role of the calcium-sensing receptor (CaR) in calcium metabolism.
- To investigate the molecular mechanisms underlying CaR dysfunction in genetic disorders.
- To understand the clinical manifestations associated with CaR mutations.
Main Methods:
- Review of literature on CaR structure, function, and mutations.
- Analysis of clinical data from patients with CaR-related disorders.
- In vitro studies examining mutant CaR function in cultured cells.
Main Results:
- Inactivating CaR mutations cause familial benign hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
- Activating CaR mutations result in autosomal dominant and sporadic hypoparathyroidism, characterized by hypocalcemia and hypercalciuria.
- Mutant CaR receptors can exhibit altered sensitivity to calcium and enhanced signal transduction.
Conclusions:
- The CaR plays a critical role in maintaining calcium balance.
- CaR mutations lead to distinct clinical phenotypes based on their activating or inactivating nature.
- Understanding CaR pathophysiology is crucial for managing calcium-related endocrine and renal diseases.