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

Am J Physiol Endocrinol Metab. 2009 Oct;297(4):E915-23. doi: 10.1152/ajpendo.00315.2009.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


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