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Cloning and Characterization of a Calcium‐Sensing Receptor from the Hypercalcemic New Zealand White Rabbit Reveals Unaltered Responsiveness to Extracellular Calcium
Author(s) -
Butters Robert R.,
Chattopadhyay Naibedya,
Nielsen Palle,
Smith Craig P.,
Mithal Ambrish,
Kifor Olga,
Bai Mei,
Quinn Steven,
Goldsmith Paul,
Hurwitz Shmuel,
Krapcho Karen,
Busby James,
Brown Edward M.
Publication year - 1997
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.1997.12.4.568
Subject(s) - extracellular , calcium sensing receptor , receptor , endocrinology , medicine , parathyroid hormone , biology , agonist , calcium , kidney , microbiology and biotechnology , biochemistry
Abstract The extracellular Ca 2+ (Ca 0 2+)‐sensing receptor (CaR) recently cloned from mammalian parathyroid, kidney, brain, and thyroid plays a central role in maintaining near constancy of Ca 0 2+. We previously showed that the hypercalcemia normally present in New Zealand white rabbits is associated with an elevated set point for Ca 0 2+‐regulated PTH release (the level of Ca 0 2+half‐maximally inhibiting hormonal secretion). This observation suggested an alteration in the Ca 0 2+‐sensing mechanism in the rabbit parathyroid, a possibility we have now pursued by isolating and characterizing the rabbit homolog of the CaR. The cloned rabbit kidney CaR (RabCaR) shares a high degree of overall homology (>90% amino acid identity) with the bovine, human, and rat CaRs, although it differs slightly in several regions of the extracellular domain potentially involved in binding ligands. By Northern analysis and/or immunohistochemistry, a similar or identical receptor is also expressed in parathyroid, thyroid C cells, small and large intestine, and in the thick ascending limb and collecting ducts of the kidney. When expressed transiently in HEK293 cells and assayed functionally through CaR agonist‐evoked increases in Ca i 2+, the rabbit CaR shows apparent affinities for Ca 0 2+, Mg 0 2+, and Gd 0 3+that are indistinguishable from those observed in studies carried out concomitantly using the human CaR. Therefore, at least as assessed by its ability to increase Ca i 2+when expressed in HEK293 cells, the intrinsic functional properties of the rabbit CaR cannot explain the hypercalcemia observed in vivo in the New Zealand white rabbit.