{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:25:02Z","timestamp":1791487502633,"version":"4.3.4"},"reference-count":47,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2009,10]]},"abstract":"<jats:p> 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<jats:sup>2+<\/jats:sup><jats:sub>o<\/jats:sub>). 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<jats:sup>+\/+<\/jats:sup> PTH<jats:sup>\u2212\/\u2212<\/jats:sup>, referred to as C<jats:sup>+<\/jats:sup>P<jats:sup>\u2212<\/jats:sup>), lacking both CaSR and PTH (CaSR<jats:sup>\u2212\/\u2212<\/jats:sup> PTH<jats:sup>\u2212\/\u2212<\/jats:sup>, C<jats:sup>\u2212<\/jats:sup>P<jats:sup>\u2212<\/jats:sup>) or wild-type (CaSR<jats:sup>+\/+<\/jats:sup> PTH<jats:sup>+\/+<\/jats:sup>, C<jats:sup>+<\/jats:sup>P<jats:sup>+<\/jats:sup>) mice to study CaSR-specific functions without confounding CaSR-mediated changes in PTH. The mice received three hypercalcemic challenges: an oral Ca<jats:sup>2+<\/jats:sup> load, injection or constant infusion of PTH via osmotic pump, or a phosphate-deficient diet. C<jats:sup>\u2212<\/jats:sup>P<jats:sup>\u2212<\/jats:sup> mice show increased susceptibility to developing hypercalcemia with all three challenges compared with the other two genotypes, whereas C<jats:sup>+<\/jats:sup>P<jats:sup>\u2212<\/jats:sup> mice defend against hypercalcemia similarly to C<jats:sup>+<\/jats:sup>P<jats:sup>+<\/jats:sup> mice. Reduced renal Ca<jats:sup>2+<\/jats:sup> clearance contributes to the intolerance of the C<jats:sup>\u2212<\/jats:sup>P<jats:sup>\u2212<\/jats:sup> mice to Ca<jats:sup>2+<\/jats:sup> loads, as they excrete less Ca<jats:sup>2+<\/jats:sup> at any given Ca<jats:sup>2+<\/jats:sup><jats:sub>o<\/jats:sub> than the other two genotypes, confirming the CaSR's direct role in regulating renal Ca<jats:sup>2+<\/jats:sup> handling. In addition, C<jats:sup>+<\/jats:sup>P<jats:sup>+<\/jats:sup> and C<jats:sup>+<\/jats:sup>P<jats:sup>\u2212<\/jats:sup>, but not C<jats:sup>\u2212<\/jats:sup>P<jats:sup>\u2212<\/jats:sup>, mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> in C<jats:sup>\u2212<\/jats:sup>P<jats:sup>\u2212<\/jats:sup> mice, in contrast, was similar to those in C<jats:sup>+<\/jats:sup>P<jats:sup>\u2212<\/jats:sup> and C<jats:sup>+<\/jats:sup>P<jats:sup>+<\/jats:sup> mice during an oral Ca<jats:sup>2+<\/jats:sup> load, indicating that increased 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> production cannot account for the oral Ca<jats:sup>2+<\/jats:sup>-induced hypercalcemia in the C<jats:sup>\u2212<\/jats:sup>P<jats:sup>\u2212<\/jats:sup> mice. Thus, CaSR-stimulated PTH release serves as a \u201cfloor\u201d to defend against hypocalcemia. In contrast, high-Ca<jats:sup>2+<\/jats:sup><jats:sub>o<\/jats:sub>-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca<jats:sup>2+<\/jats:sup><jats:sub>o<\/jats:sub>-stimulated, CaSR-mediated CT secretion and renal Ca<jats:sup>2+<\/jats:sup> excretion, and perhaps other factors, serve as a \u201cceiling\u201d to limit hypercalcemia resulting from various types of hypercalcemic challenges. <\/jats:p>","DOI":"10.1152\/ajpendo.00315.2009","type":"journal-article","created":{"date-parts":[[2009,7,28]],"date-time":"2009-07-28T22:29:05Z","timestamp":1248820145000},"page":"E915-E923","source":"Crossref","is-referenced-by-count":131,"title":["The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion"],"prefix":"10.1152","volume":"297","author":[{"given":"Lakshmi","family":"Kantham","sequence":"first","affiliation":[{"name":"Division of Endocrinology, 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