The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion.
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.
Kantham
Lakshmi
L
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. lkantham@gmail.com
Quinn
Steven J
SJ
Egbuna
Ogo I
OI
Baxi
Khanjan
K
Butters
Robert
R
Pang
Jian L
JL
Pollak
Martin R
MR
Goltzman
David
D
Brown
Edward M
EM
D000596:Amino Acids / Q000652:urine; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002112:Calcifediol / Q000378:metabolism; D002116:Calcitonin / Q000097:blood; D002118:Calcium / Q000097:blood / Q000494:pharmacology / Q000652:urine; D004343:Drug Implants; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006934:Hypercalcemia / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015675:Osteocalcin / Q000097:blood; D010281:Parathyroid Hormone / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D010710:Phosphates / Q000172:deficiency; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000502:physiology*
D000596:Amino Acids; D004343:Drug Implants; D010281:Parathyroid Hormone; D010710:Phosphates; D044169:Receptors, Calcium-Sensing; D015675:Osteocalcin; C036020:deoxypyridinoline; D002116:Calcitonin; D002112:Calcifediol; D002118:Calcium