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

Area of Science:

• Physiology
• Molecular Biology
• Genetics

Background:

• The calcium-sensing receptor (CaR) is critical for maintaining mineral ion homeostasis by sensing extracellular calcium (Ca2+o).
• CaR plays a vital role in parathyroid function and the renal handling of calcium and magnesium.
• Dysregulation of CaR function leads to genetic disorders such as familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia.

Purpose of the Study:

• To investigate the structure, function, and physiological roles of the calcium-sensing receptor (CaR).
• To understand the impact of CaR mutations on mineral ion homeostasis and related diseases.
• To explore the CaR's involvement in renal water handling and its function as an extracellular messenger.

Main Methods:

• Expression cloning in Xenopus laevis oocytes to isolate the CaR cDNA.
• Identification and characterization of CaRs across various species and tissues.
• Analysis of patient data with CaR mutations to understand physiological consequences.

Main Results:

• The CaR is a G protein-coupled receptor with a distinct structure, highly expressed in parathyroid cells, kidneys, brain, and GI tract.
• Loss-of-function CaR mutations cause resistance to Ca2+o, leading to hypercalcemia (e.g., FHH), while activating mutations cause hypocalcemia.
• CaR significantly influences renal Ca2+ and Mg2+ reabsorption and regulates renal water handling, coordinating mineral and water balance.

Conclusions:

• The CaR is a key regulator of systemic calcium homeostasis and renal divalent ion handling.
• CaR mutations result in distinct inherited disorders of calcium metabolism.
• Beyond homeostasis, the CaR acts as an extracellular Ca2+ messenger in diverse tissues, including the brain and eye.