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J. Biol. Chem., Vol. 279, Issue 37, 38151-38159, September 10, 2004

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L-Amino Acids Regulate Parathyroid Hormone Secretion^*

Arthur D. Conigrave¶, Hee-Chang Mun, Leigh Delbridge||, Stephen J. Quinn**, Margaret Wilkinson||, and Edward M. Brown**

From the School of Molecular and Microbial Biosciences, University of Sydney, New South Wales 2006, Australia, the ^||Departments of Surgery and Endocrinology, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia, and the ^**Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Parathyroid hormone (PTH) secretion is acutely regulated by the extracellular Ca²⁺-sensing receptor (CaR). Thus, Ca²⁺ ions, and to a lesser extent Mg²⁺ ions, have been viewed as the principal physiological regulators of PTH secretion. Herein we show that in physiological concentrations, L-amino acids acutely and reversibly activated the extracellular Ca²⁺-sensing receptor in normal human parathyroid cells and inhibited parathyroid hormone secretion. Individual L-amino acids, especially of the aromatic and aliphatic classes, as well as plasma-like amino acid mixtures, stereoselectively mobilized Ca²⁺ ions in normal human parathyroid cells in the presence but not the absence of the CaR agonists, extracellular Ca²⁺ (Ca²⁺_o), or spermine. The order of potency was L-Trp = L-Phe > L-His > L-Ala > L-Glu > L-Arg = L-Leu. CaR-active amino acids also acutely and reversibly suppressed PTH secretion at physiological ionized Ca²⁺ concentrations. At a Ca²⁺_o of 1.1 mM and an amino acid concentration of 1 mM, CaR-active amino acids (L-Phe = L-Trp > L-His = L-Ala), but not CaR-inactive amino acids (L-Leu and L-Arg), stereoselectively suppressed PTH secretion by up to 40%, similar to the effect of raising Ca²⁺_o to 1.2 mM. A physiologically relevant increase in the -fold concentration of the plasma-like amino acid mixture (from 1x to 2x) also reversibly suppressed PTH secretion in the Ca²⁺_o concentration range 1.05–1.25 mM. In conclusion, L-amino acids acutely and reversibly activate endogenous CaRs and suppress PTH secretion at physiological concentrations. The results indicate that L-amino acids are physiological regulators of PTH secretion and thus whole body calcium metabolism.

Received for publication, June 8, 2004

^* This work was supported by the NHMRC of Australia and Grants DK41415, DK48330, and DK52005 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^¶ Received early mentoring in endocrine research from Prof. Niels A. Thorn of the University of Copenhagen, Denmark. To whom correspondence should be addressed: School of Molecular and Microbial Biosciences (G08), University of Sydney, New South Wales 2006, Australia. Fax: 612-9351-4726; E-mail: a.conigrave{at}mmb.usyd.edu.au.

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