Abstract
Cellular sensing of L-amino acids is widespread and controls diverse cellular responses regulating, for example, rates of hormone secretion, amino acid uptake, protein synthesis and protein degradation (autophagy). However, the nature of the sensing mechanisms involved has been elusive. One important sensing mechanism is selective for branched chain amino acids, acts via mTOR (mammalian target of rapamycin) and regulates the rates of insulin and IGF-1 secretion as well as hepatic, and possibly muscle, autophagy. A second sensing mechanism is selective for aromatic L-amino acids and regulates the rate of gastric acid secretion and other responses in the gastro-intestinal tract. Interactions between calcium and protein metabolism, including accelerated urinary calcium excretion in subjects consuming high-protein diets and secondary hyperparathyroidism in subjects consuming low-protein diets, suggest an additional amino acid sensing mechanism linked to the control of urinary calcium excretion and parathyroid hormone (PTH) release.
New data demonstrating L-amino acid-dependent activation of the calcium-sensing receptor (CaR), which regulates PTH secretion and urinary calcium excretion, suggests an unexpected explanation for these links between calcium and protein metabolism. Furthermore, expression of the CaR in gastrin-secreting G-cells and acid-secreting parietal cells, together with data indicating that the CaR exhibits selectivity for aromatic amino acids, would appear to provide a molecular explanation for amino acid sensing in the gastrointestinal tract. This review examines what is known about the CaR as a gene, a receptor, a physiological regulator and, now, as an amino acid sensor. Possible new roles for the CaR are also considered.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Allen LH, Oddoye EA, Margen S . 1979 Protein-induced hypercalciuria: a longer term study Am. J. Clin. Nutr. 32: 741–749
Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S . 1996 Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor J. Clin. Invest. 97: 1085–1093
Bonadonna RC, Saccomani MP, Cobelli C, DeFronzo RA . 1993 Effect of insulin on system A amino acid transport in human skeletal muscle J. Clin. Invest. 91: 514–521
Bonjour JP, Schurch MA, Chevalley T, Ammann P, Rizzoli R . 1997 Protein intake, IGF-1 and osteoporosis Osteopor. Int. 7: (Suppl 3): S36–42
Bradbury RA, Sunn KL, Crossley MC, Bai M, Brown EM, Delbridge L, Conigrave AD . 1998 Expression of the parathyroid Ca2+ sensing receptor in cytotrophoblasts from human term placenta J. Endocrinol. 156: 425–430
Brauner-Osborne H, Jensen AA, Sheppard PO, O'Hara P, Krogsgaard-Larsen P . 1999 The agonist-binding domain of the calcium-sensing receptor is located at the amino-terminal domain J. Biol. Chem. 274: 18382–18386
Brown EM, Hebert SC . 1996 A cloned extracellular Ca(2+)-sensing receptor: molecular mediator of the actions of extracellular Ca2+ on parathyroid and kidney cells? Kidney Int. 49: 1042–1046
Brown EM, MacLeod RJ . 2001 Extracellular calcium sensing and extracellular calcium signaling Physiol. Rev. 81: 239–297
Bruce JI, Yang X, Ferguson CJ, Elliott AC, Steward MC, Case RM, Riccardi D . 1999 Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing receptor in rat pancreas J. Biol. Chem. 274: 20561–20568
Calvo MS, Esatell R, Offord KP, Bergstralh EJ, Burritt MF . 1991 Circadian variation in ionized calcium and intact parathyroid hormone: evidence for sex differences in calcium homeostasis J. Clin. Endocrinol. Metab. 72: 69–76
Canaff L, Petit JL, Kisiel M, Watson PH, Gascon-Barre M, Hendy GN . 2001 Extracellular calcium-sensing receptor is expressed in rat hepatocytes, coupling to intracellular calcium mobilization and stimulation of bile flow J. Biol. Chem. 276: 4070–4079
Chattopadhyay N, Legradi G, Bai M, Kifor O, Ye C, Vassilev PM, Brown EM, Lechan RM . 1997 Calcium-sensing receptor in the rat hippocampus: a developmental study Devl. Brain Res. 100: 13–21
Chattopadhyay N, Cheng I, Rogers K, Riccardi D, Hall A, Diaz R, Hebert SC, Soybel DI, Brown EM . 1998a Identification and localization of extracellular Ca2+-sensing receptor in rat intestine Am. J. Physiol. 274: G122–G130
Chattopadhyay N, Ye CP, Yamaguchi T, Kifor O, Vassilev PM, Nishimura R, Brown EM . 1998b Extracellular calcium-sensing receptor in rat oligodendrocytes: expression and potential role in regulation of cellular proliferation and an outward K+ channel Glia 24: 449–458
Cheng I, Klingensmith ME, Chattopadhyay N, Kifor O, Butters RR, Soybel DI, Brown EM . 1998 Identification and localization of the extracellular calcium-sensing receptor in human breast J. Clin. Endocrinol. Metab. 83: 703–707
Conigrave AD, Quinn SJ, Brown EM . 2000a Cooperative multi-modal sensing and therapeutic implications of the extracellular Ca2+-sensing receptor Trends Pharm. Sci. 21: 401–407
Conigrave AD, Quinn SJ, Brown EM . 2000b L-Amino acid sensing by the extracellular Ca2+-sensing receptor Proc. Natl. Acad. Sci. USA 97: 4814–4819
Fafournoux P, Bruhat A, Jousse C . 2000 Amino acid regulation of gene expression Biochem. J. 351: 1–12
Feigin RD, Klainer AS, Beisel WR . 1967 Circadian periodicity of blood amino-acids in adult men Nature 215: 512–514
Fernstrom JD, Wurtman RJ, Hammarstrom-Wiklund B, Rand WM, Munro HN, Davidson CS . 1979 Diurnal variations in plasma concentrations of tryptophan, tyrosine, and other neutral amino acids: effect of dietary protein intake Am. J. Clin. Nutr. 32: 1912–1922
Ferry S, Traiffort E, Stinnakre J, Ruat M . 2000 Developmental and adult expression of rat calcium-sensing receptor transcripts in neurons and oligodendrocytes Eur. J. Neurosci. 12: 872–884
Fraser WD, Logue FC, Christie JP, Cameron DA, O'Reilly DSJ, Beastall GH . 1994 Alteration of the circadian rhythm of intact parathyroid hormone following a 96-hour fast Clin. Endocrinol. 40: 523–528
Gama L, Baxendale-Cox LM, Breitwieser GE . 1997 Ca2+-sensing receptors in intestinal epithelium Am. J. Physiol. 273: C1168–C1175
Geibel JP, Wagner CA, Caroppo R, Qureshi I, Gloeckner J, Manuelidis L, Kirchhoff P, Radebold K . 2001 The stomach divalent ion sensing receptor (SCAR) is a modulator of gastric acid secretion J. Biol. Chem. 276: 39549–39552
Hodsman AB, Fraher LJ, Ostbye T, Adachi JD, Steer BM . 1993 An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis J. Clin. Invest. 91: 1138–1148
House MG, Kohlmeier L, Chattopadhyay N, Kifor O, Yamaguchi T, Leboff MS, Glowacki J, Brown EM . 1997 Expression of an extracellular calcium-sensing receptor in human and mouse bone marrow cells J. Bone Miner. Res. 12: 1959–1970
Isenberg JI, Maxwell V . 1978 Intravenous infusion of amino acids stimulates gastric acid secretion in man New Engl. J. Med. 298: 27–29
Johnson NE, Alcantara EN, Linkswiler H . 1970 Effect of level of protein intake on urinary and fecal calcium and calcium retention of young adult males J. Nutr. 100: 1425–1430
Jurbiz W, Canterbury JM, Reiss E, Tyler FH . 1972 Circadian rhythm in serum parathyroid hormone concentration in human subjects: correlation with serum calcium, phosphate, albumin, and growth hormone levels J. Clin. Invest. 51: 2040–2046
Kerstetter JE, Allen LH . 1990 Dietary protein increases urinary calcium [See comments.] J. Nutr. 120: 134–136
Kerstetter JE, Allen LH . 1994 Protein intake and calcium homeostasis Adv. Nutr. Res. 9: 167–181
Kerstetter JE, Caseria DM, Mitnick ME, Ellison AF, Gay LF, Liskov TAP, Carpenter TO, Insogna KL . 1997 Increased circulating concentrations of parathyroid hormone in healthy, young women consuming a protein-restricted diet Am. J. Clin. Nutr. 66: 1188–1196
Kerstetter JE, O'Brien KO, Insogna KL . 1998 Dietary protein affects intestinal calcium absorption Am. J. Clin. Nutr. 68: 859–865
Kerstetter JE, Looker AC, Insogna KL . 2000a Low dietary protein and low bone density Calcif. Tissue Int. 66: 313
Kerstetter JE, Svastisalee CM, Caseria DM, Mitnick ME, Insogna KL . 2000b A threshold for low-protein-diet-induced elevations in parathyroid hormone Am. J. Clin. Nutr. 72: 168–173
Konturek SJ, Tasler J, Cieszkowski M, Jaworek J . 1978 Comparison of intravenous amino acids in the stimulation of gastric secretion Gastroenterology 75: 817–824
Kovacs CS, Ho-Pao CL, Hunzelman JL, Lanske B, Fox J, Seidman JG, Seidman CE, Kronenberg HM . 1998 Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor J. Clin. Invest. 101: 2812–2820
Levy HL . 1999 Phenylketonuria: old disease, new approach to treatment Proc. Natl Acad. Sci. USA 96: 1811–1813
Lindenau K, Kokot F, Frohling PY . 1986 Suppression of parathyroid hormone by therapy with a mixture of keto analogues/amino acids in hemodialysis patients Nephron 43: 84–86
Markowitz ME, Arnaud S, Rosen JF, Thorpy M, Laximinarayan S . 1988 Temporal interrelationships between the circadian rhythms of serum parathyroid hormone and calcium concentrations J. Clin. Endocrinol. Metab. 67: 1068–1073
McArthur KE, Isenberg JI, Hogan DL, Dreier SJ . 1983 Intravenous infusion of L-isomers of phenylalanine and tryptophan stimulate gastric acid secretion at physiologic plasma concentrations in normal subjects and after parietal cell vagotomy J. Clin. Invest. 71: 1254–1262
Oda Y, Tu CL, Pillai S, Bikle DD . 1998 The calcium sensing receptor and its alternatively spliced form in keratinocyte differentiation J. Biol. Chem. 273: 23344–23352
O'Hara PJ, Sheppard PO, Thogersen H, Venezia D, Haldeman BA, McGrane V, Houamed KM, Thomsen C, Gilbert TL, Mulvihill ER . 1993 The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins Neuron 11: 41–52
Ray J, Squires P, Curtis S, Meloche M, Buchan A . 1997 Expression of the calcium-sensing receptor on human antral gastrin cells in culture J. Clin. Invest. 99: 2328–2333
Riccardi D, Traebert M, Ward DT, Kaissling B, Biber J, Hebert SC, Murer H . 2000 Dietary phosphate and parathyroid hormone alter the expression of the calcium-sensing receptor (CaR) and the Na+-dependent Pi transporter (NaPi−2) in the rat proximal tubule Pflugers Arch. 441: 379–387
Ruat M, Molliver ME, Snowman AM, Snyder SH . 1995 Calcium-sensing receptor: molecular cloning in rat and localization to nerve terminals Proc. Natl Acad. Sci. USA 92: 3161–3165
Rutten MJ, Bacon KD, Marlink KL, Stoney M, Meichsner CL, Lee FP, Hobson SA, Rodland KD, Sheppard BC, Trunkey DD, Deveney KE, Deveney CW . 1999 Identification of a functional Ca2+-sensing receptor in normal human gastric mucous epithelial cells Am. J. Physiol 277: G662–670
Sands JM, Naruse M, Baum M, Jo I, Hebert SC, Brown EM, Harris HW . 1997 Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct J. Clin. Invest. 99: 1399–1405
Sherman HC . 1920 Calcium requirements of maintenance in man J. Biol. Chem. 44: 21–27
Taylor IL, Byrne WJ, Christie DL, Ament ME, Walsh JH . 1982 Effect of individual L-amino acids on gastric acid secretion and serum gastrin and pancreatic polypeptide release in humans Gastroenterology 83: 273–278
Van Sluijters DA, Dubbelhuis PF, Blommaart EFC, Meijer AJ . 2000 Amino-acid-dependent signal transduction Biochem. J. 351: 545–550
Wollheim C, Biden T . 1986 Signal transduction in insulin secretion: comparison between fuel stimuli and receptor agonists Ann. NY Acad. Sci. 488: 317–333
Wurtman RJ, Rose CM, Chou C, Larin FF . 1968 Daily rhythms in the concentrations of various amino acids in human plasma New Engl. J. Med. 279: 171–175
Acknowledgements
The authors' research is supported by the NH&MRC of Australia and the NIH of the USA (DK41415, 48330 and 52005).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Conigrave, A., Franks, A., Brown, E. et al. L-Amino acid sensing by the calcium-sensing receptor: a general mechanism for coupling protein and calcium metabolism?. Eur J Clin Nutr 56, 1072–1080 (2002). https://doi.org/10.1038/sj.ejcn.1601463
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ejcn.1601463
Keywords
This article is cited by
-
MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR
Scientific Reports (2018)
-
l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents
International Journal of Obesity (2017)
-
Protein/amino-acid modulation of bone cell function
BoneKEy Reports (2016)
-
The calcium sensing receptor: from calcium sensing to signaling
Science China Life Sciences (2015)
-
Calcium-sensing receptor
AfCS-Nature Molecule Pages (2008)