The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion.

Abstract

The calcium-sensing receptor (CaSR) controls parathyroid hormone (PTH) secretion, which, in turn, via direct and indirect actions on kidney, bone, and intestine, maintains a normal extracellular ionized calcium concentration (Ca(2+)(o)). There is less understanding of the CaSR's homeostatic importance outside of the parathyroid gland. We have employed single and double knockout mouse models, namely mice lacking PTH alone (CaSR(+/+) PTH(-/-), referred to as C(+)P(-)), lacking both CaSR and PTH (CaSR(-/-) PTH(-/-), C(-)P(-)) or wild-type (CaSR(+/+) PTH(+/+), C(+)P(+)) mice to study CaSR-specific functions without confounding CaSR-mediated changes in PTH. The mice received three hypercalcemic challenges: an oral Ca(2+) load, injection or constant infusion of PTH via osmotic pump, or a phosphate-deficient diet. C(-)P(-) mice show increased susceptibility to developing hypercalcemia with all three challenges compared with the other two genotypes, whereas C(+)P(-) mice defend against hypercalcemia similarly to C(+)P(+) mice. Reduced renal Ca(2+) clearance contributes to the intolerance of the C(-)P(-) mice to Ca(2+) loads, as they excrete less Ca(2+) at any given Ca(2+)(o) than the other two genotypes, confirming the CaSR's direct role in regulating renal Ca(2+) handling. In addition, C(+)P(+) and C(+)P(-), but not C(-)P(-), mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)(2)D(3) in C(-)P(-) mice, in contrast, was similar to those in C(+)P(-) and C(+)P(+) mice during an oral Ca(2+) load, indicating that increased 1,25(OH)(2)D(3) production cannot account for the oral Ca(2+)-induced hypercalcemia in the C(-)P(-) mice. Thus, CaSR-stimulated PTH release serves as a "floor" to defend against hypocalcemia. In contrast, high-Ca(2+)(o)-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca(2+)(o)-stimulated, CaSR-mediated CT secretion and renal Ca(2+) excretion, and perhaps other factors, serve as a "ceiling" to limit hypercalcemia resulting from various types of hypercalcemic challenges.

• Authors: Lakshmi Kantham, Steven J Quinn, Ogo I Egbuna, Khanjan Baxi, Robert Butters, Jian L Pang, Martin R Pollak, David Goltzman, Edward M Brown
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 297 Issue 4 Pg. E915-23 (Oct 2009) ISSN: 1522-1555 [Electronic] United States
• PMID: 19797241 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amino Acids
• Drug Implants
• Parathyroid Hormone
• Phosphates
• Receptors, Calcium-Sensing
• Osteocalcin
• deoxypyridinoline
• Calcitonin
• Calcifediol
• Calcium

Topics

• Amino Acids (urine)
• Animals
• Bone and Bones (metabolism)
• Calcifediol (metabolism)
• Calcitonin (blood)
• Calcium (blood, pharmacology, urine)
• Drug Implants
• Homeostasis (genetics, physiology)
• Hypercalcemia (physiopathology)
• Kidney (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteocalcin (blood)
• Parathyroid Hormone (genetics, pharmacology, physiology)
• Phosphates (deficiency)
• Receptors, Calcium-Sensing (genetics, physiology)