Co-Authors:
Butters, R.R., Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States, Endocrine-Hypertension Division, Brigham and Women 's Hospital, 221 Longwood Avenue, Boston, MA 02115, United States
Chattopadhyay, N., Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
Nielsen, F., Division of Nephrology, Righospitalet, Copenhagen, Denmark
Smith, C.P., School of Biological Sciences, University of Manchester, Manchester, United Kingdom
Mithal, A., Department of Endocrinology, Sanjay Gandhi Inst. of Med. Sciences, Lucknow, India
Kifor, O., Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
Bai, M., Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
Quinn, S., Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
Goldsmith, P., Molecular Pathophysiology Branch, NIDDK, NIH, Bethesda, MD, United States
Hurwitz, S., Volcani Center, Institute of Animal Sciences, Bet Dagan, Israel
Krapcho, K., NPS Pharmaceuticals, Inc, Salt Lake City, UT, United States
Busby, J., NPS Pharmaceuticals, Inc, Salt Lake City, UT, United States
Brown, E.M., Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
Abstract:
The extracellular Ca2+ (Ca0/2+)-sensing receptor (CAR) recently cloned from mammalian parathyroid, kidney, brain, and thyroid plays a central role in maintaining near constancy of Ca0/2+. We previously showed that the hypercalcemia normally present in New Zealand white rabbits is associated with an elevated set point for Ca0/2+-regulated PTH release (the level of Ca0/2+ half-maximally inhibiting hormonal secretion). This observation suggested an alteration in the Ca0/2+-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 Ca0/2+, Mg0/2+, and Gd0/3+ 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.
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