Skip to main content
SpringerLink
Log in

Calcium receptor signaling and citrate transport

  • Original Paper
  • Published:
Urolithiasis Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

The calcium sensing receptor (CaSR) in the distal nephron decreases the propensity for calcium stones. Here we investigate if the apical CaSR in the proximal tubule also prevents stone formation acting via regulation of apical dicarboxylate and citrate transport. Urinary citrate, partially reabsorbed as a dicarboxylate in the proximal tubule lumen, inhibits stone formation by complexing calcium. We previously demonstrated a novel apical calcium-sensitive dicarboxylate transport system in OK proximal tubule cells. This calcium-sensitive process has the potential to modulate the amount of citrate available to complex increased urinary calcium. Using isotope labeled succinate uptake in OK cells along with various pharmacologic tools we examined whether the CaSR alters apical dicarboxylate transport and through which signal transduction pathways this occurs. Our results indicate that in the proximal tubule CaSR adjusts apical dicarboxylate transport, and does so via a CaSR → Gq → PKC signaling pathway. Thus, the CaSR may decrease the propensity for stone formation via actions in both proximal and distal nephron segments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Notes

  1. Complicating this interpretation, NaDC1 has been considered responsible for all citrate reabsrorption on the apical side of the proximal tube. We have previously shown that NaDC1 ex vivo is not calcium-sensitive. So whether the calcium sensitive transport is NaDC1 or not remains unknown.

References

  1. Egbuna O, Quinn S, Kantham L, Butters R, Pang J, Pollak M, Goltzman D, Brown E (2009) The full-length calcium-sensing receptor dampens the calcemic response to 1alpha,25(OH)2 vitamin D3 in vivo independently of parathyroid hormone. Am J Physiol Renal Physiol 297(3):F720–F728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Quamme GA (1982) Effect of hypercalcemia on renal tubular handling of calcium and magnesium. Can J Physiol Pharmacol 60(10):1275–1280

    Article  CAS  PubMed  Google Scholar 

  3. Riccardi D, Brown EM (2010) Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol 298(3):F485–F499

    Article  CAS  PubMed  Google Scholar 

  4. Wang WH, Lu M, Hebert SC (1996) Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL. Am J Physiol 271(1 Pt 1):C103–C111

    Article  CAS  PubMed  Google Scholar 

  5. Topala CN, Schoeber JP, Searchfield LE, Riccardi D, Hoenderop JG, Bindels RJ (2009) Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2 + channel TRPV5. Cell Calcium 45(4):331–339

    Article  CAS  PubMed  Google Scholar 

  6. Renkema KY, Velic A, Dijkman HB, Verkaart S, van der Kemp AW, Nowik M, Timmermans K, Doucet A, Wagner CA, Bindels RJ, Hoenderop JG (2009) The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis. J Am Soc Nephrol 20(8):1705–1713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Riccardi D, Hall AE, Chattopadhyay N, Xu JZ, Brown EM, Hebert SC (1998) Localization of the extracellular Ca2+/polyvalent cation-sensing protein in rat kidney. Am J Physiol 274(3 Pt 2):F611–F622

    CAS  PubMed  Google Scholar 

  8. Conigrave AD, Ward DT (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab 27(3):315–331

    Article  CAS  PubMed  Google Scholar 

  9. Remy C, Kirchhoff P, Hafner P, Busque SM, Müeller MK, Geibel JP, Wagner CA (2007) Stimulatory pathways of the calcium-sensing receptor on acid secretion in freshly isolated human gastric glands. Cell Physiol Biochem 19(1–4):33–42

    Article  CAS  PubMed  Google Scholar 

  10. Capasso G, Geibel PJ, Damiano S, Jaeger P, Richards WG, Geibel JP (2013) The calcium sensing receptor modulates fluid reabsorption and acid secretion in the proximal tubule. Kidney Int 84(2):277–284

    Article  CAS  PubMed  Google Scholar 

  11. Pajor AM (1999) Sodium-coupled transporters for Krebs cycle intermediates. Annu Rev Physiol 61:663–682

    Article  CAS  PubMed  Google Scholar 

  12. Bai XY, Chen X, Sun AQ, Feng Z, Hou K, Fu B (2007) Membrane topology structure of human high-affinity, sodium-dependent dicarboxylate transporter. FASEB J 21(10):2409–2417

    Article  CAS  PubMed  Google Scholar 

  13. Pajor AM (1999) Citrate transport by the kidney and intestine. Semin Nephrol 19(2):195–200

    CAS  PubMed  Google Scholar 

  14. Brennan TS, Klahr S, Hamm LL (1986) Citrate transport in rabbit nephron. Am J Physiol 251(4 Pt 2):F683–F689

    CAS  PubMed  Google Scholar 

  15. Hering-Smith KS, Gambala CT, Hamm LL (2000) Citrate and succinate transport in proximal tubule cells. Am J Physiol Renal Physiol 278(3):F492–F498

    Article  CAS  PubMed  Google Scholar 

  16. Hering-Smith KS, Schiro FR, Pajor AM, Hamm LL (2011) Calcium sensitivity of dicarboxylate transport in cultured proximal tubule cells. Am J Physiol Renal Physiol 300(2):F425–F432

    Article  CAS  PubMed  Google Scholar 

  17. Hering-Smith KS, Mao W, Schiro FR, Coleman-Barnett J, Pajor AM, Hamm LL (2014) Localization of the calcium-regulated citrate transport process in proximal tubule cells. Urolithiasis 42(3):209–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Law D, Hering-Smith KS, Hamm LL (1992) Citrate transport in proximal cell line. Am J Physiol 263(1 Pt 1):C220–C225

    Article  CAS  PubMed  Google Scholar 

  19. Hofer AM, Brown EM (2003) Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol 4(7):530–538

    Article  CAS  PubMed  Google Scholar 

  20. Hernández-Bedolla MA, González-Domínguez E, Zavala-Barrera C, Gutiérrez-López TY, Hidalgo-Moyle JJ, Vázquez-Prado J, Sánchez-Torres C, Reyes-Cruz G (2016) Calcium-sensing-receptor (CaSR) controls IL-6 secretion in metastatic breast cancer MDA-MB-231 cells by a dual mechanism revealed by agonist and inverse-agonist modulators. Mol Cell Endocrinol 436:159–168

    Article  PubMed  CAS  Google Scholar 

  21. Zhu Y, He Q, Aydin C, Rubera I, Tauc M, Chen M, Weinstein LS, Marshansky V, Jüppner H, Bastepe M (2016) Ablation of the stimulatory G protein α-subunit in renal proximal tubules leads to parathyroid hormone-resistance with increased renal Cyp24a1 mRNA abundance and reduced serum 1,25-dihydroxyvitamin D. Endocrinology 157(2):497–507

    Article  CAS  PubMed  Google Scholar 

  22. Rangel LB, Lopes AG, Lara LS, Carvalho TL, Silva IV, Oliveira MM, Einicker-Lamas M, Vieyra A, Nogaroli L, Caruso-Neves C (2005) PI-PLCbeta is involved in the modulation of the proximal tubule Na+-ATPase by angiotensin II. Regul Pept 127(1–3):177–182

    Article  CAS  PubMed  Google Scholar 

  23. Wu DQ, Lee CH, Rhee SG, Simon MI (1992) Activation of phospholipase C by the alpha subunits of the Gq and G11 proteins in transfected Cos-7 cells. J Biol Chem 267(3):1811–1817

    CAS  PubMed  Google Scholar 

  24. Nasman J, Kukkonen JP, Ammoun S, Akerman KE (2001) Role of G-protein availability in differential signaling by alpha 2-adrenoceptors. Biochem Pharmacol 62(7):913–922

    Article  CAS  PubMed  Google Scholar 

  25. Brennan SC, Thiem U, Roth S, Aggarwal A, Fetahu IS, Tennakoon S, Gomes AR, Brandi ML, Bruggeman F, Mentaverri R, Riccardi D, Kallay E (2013) Calcium sensing receptor signalling in physiology and cancer. Biochim Biophys Acta 1833(7):1732–1744

    Article  CAS  PubMed  Google Scholar 

  26. Petrel C, Kessler A, Dauban P, Dodd RH, Rognan D, Ruat M (2004) Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J Biol Chem 279(18):18990–18997

    Article  CAS  PubMed  Google Scholar 

  27. Harriman JF, Liu XL, Aleo MD, Machaca K, Schnellmann RG (2002) Endoplasmic reticulum Ca(2+) signaling and calpains mediate renal cell death. Cell Death Differ 9(7):734–741

    Article  CAS  PubMed  Google Scholar 

  28. Beckman ML, Bernstein EM, Quick MW (1999) Multiple G protein-coupled receptors initiate protein kinase C redistribution of GABA transporters in hippocampal neurons. J Neurosci 19(11):RC9

    Article  CAS  PubMed  Google Scholar 

  29. Forster IC, Traebert M, Jankowski M, Stange G, Biber J, Murer H (1999) Protein kinase C activators induce membrane retrieval of type II Na+-phosphate cotransporters expressed in Xenopus oocytes. J Physiol 517(Pt 2):327–340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Emery AC, Eiden MV, Eiden LE (2013) A new site and mechanism of action for the widely used adenylate cyclase inhibitor SQ22,536. Mol Pharmacol 83:95–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yamaguchi T et al (2003) Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 63:1983–1994

    Article  CAS  PubMed  Google Scholar 

  32. Siebler T et al (1996) Pertussis toxin sensitive G-proteins are not involved in the mitogenic signaling pathway of insulin-like growth factor-I in normal rat kidney epithelial (NRKE) cells. Regul Pept 62:65–71

    Article  CAS  PubMed  Google Scholar 

  33. Wang D, McGiff JC, Ferreri NR (2000) Regulation of cyclooxygenase isoforms in the renal thick ascending limb: effects of extracellular calcium. J Physiol Pharmacol 51(4 Pt 1):587–595

    Article  CAS  PubMed  Google Scholar 

  34. Kifor O, MacLeod RJ, Diaz R, Bai M, Yamaguchi T, Yao T, Kifor I, Brown EM (2001) Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and CaR-transfected HEK293 cells. Am J Physiol Renal Physiol 280(2):F291–F302

    Article  CAS  PubMed  Google Scholar 

  35. Kempson SA, Edwards JM, Sturek M (2006) Inhibition of the renal betaine transporter by calcium ions. Am J Physiol Renal Physiol 291(2):F305–F313

    Article  CAS  PubMed  Google Scholar 

  36. Hagos Y, Burckhardt BC, Larsen A, Mathys C, Gronow T, Bahn A, Wolff NA, Burckhardt G, Steffgen J (2004) Regulation of sodium-dicarboxylate cotransporter-3 from winter flounder kidney by protein kinase C. Am J Physiol Renal Physiol 286(1):F86–F93

    Article  CAS  PubMed  Google Scholar 

  37. Wolff NA, Thies K, Kuhnke N, Reid G, Friedrich B, Lang F, Burckhardt G (2003) Protein kinase C activation downregulates human organic anion transporter 1-mediated transport through carrier internalization. J Am Soc Nephrol 14(8):1959–1968

    Article  CAS  PubMed  Google Scholar 

  38. Pajor AM, Sun N (1999) Protein kinase C-mediated regulation of the renal Na(+)/dicarboxylate cotransporter, NaDC-1. Biochim Biophys Acta 1420(1–2):223–230

    Article  CAS  PubMed  Google Scholar 

  39. Collins TP, Terrar DA (2012) Ca(2+)-stimulated adenylyl cyclases regulate the L-type Ca(2+) current in guinea-pig atrial myocytes. J Physiol 590(8):1881–1893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li X, Guo Q, Gao J, Yang J, Zhang W, Liang Y, Wu D, Liu Y, Weng J, Li Q, Zhang Y (2013) The adenylyl cyclase inhibitor MDL-12,330A potentiates insulin secretion via blockade of voltage-dependent K(+) channels in pancreatic beta cells. PLoS One 8(10):e77934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dal Molin F, Zornetta I, Puhar A, Tonello F, Zaccolo M, Montecucco C (2008) cAMP imaging of cells treated with pertussis toxin, cholera toxin, and anthrax edema toxin. Biochem Biophys Res Commun 376(2):429–433

    Article  CAS  PubMed  Google Scholar 

  42. Gadea A, López E, López-Colomé AM (1999) The adenylate cyclase inhibitor MDL-12330A has a non-specific effect on glycine transport in Müller cells from the retina. Brain Res 838(1–2):200–204

    Article  CAS  PubMed  Google Scholar 

  43. Lippe C, Ardizzone C (1991) Actions of vasopressin and isoprenaline on the ionic transport across the isolated frog skin in the presence and the absence of adenyl cyclase inhibitors MDL12330A and SQ22536. Comp Biochem Physiol C 99(1–2):209–211

    Article  CAS  PubMed  Google Scholar 

  44. Rampe D, Triggle DJ, Brown AM (1987) Electrophysiologic and biochemical studies on the putative Ca++ channel blocker MDL 12,330A in an endocrine cell. J Pharmacol Exp Ther 243(1):402–407

    CAS  PubMed  Google Scholar 

  45. Brennan S, Hering-Smith K, Hamm LL (1988) Effect of pH on citrate reabsorption in the proximal convoluted tubule. Am J Physiol 255(2 Pt 2):F301-306

    Google Scholar 

  46. Hamm LL, Hering-Smith KS (2002) Pathophysiology of hypocitraturic nephrolithiasis. Endocrinol Metab Clin North Am 31(4):885–893 viii

    Article  CAS  PubMed  Google Scholar 

  47. Peti-Peterdi J (2013) Mitochondrial TCA cycle intermediates regulate body fluid and acid–base balance. J Clin Invest 123(7):2788–2790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Magno AL, Ward BK, Ratajczak T (2011) The calcium-sensing receptor: a molecular perspective. Endocr Rev 32(1):3–30

    Article  CAS  PubMed  Google Scholar 

  49. Chang W, Shoback D (2004) Extracellular Ca2+-sensing receptors—an overview. Cell Calcium 35(3):183–196

    Article  CAS  PubMed  Google Scholar 

  50. Kenakin T (2011) Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 336(2):296–302

    Article  CAS  PubMed  Google Scholar 

  51. Thomsen AR, Hvidtfeldt M, Bräuner-Osborne H (2012) Biased agonism of the calcium-sensing receptor. Cell Calcium 51(2):107–116

    Article  CAS  PubMed  Google Scholar 

  52. Thomsen AR, Worm J, Jacobsen SE, Stahlhut M, Latta M, Bräuner-Osborne H (2012) Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6–23 cells. J Pharmacol Exp Ther 343(3):638–649

    Article  CAS  PubMed  Google Scholar 

  53. Davey AE, Leach K, Valant C, Conigrave AD, Sexton PM, Christopoulos A (2012) Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology 153(3):1232–1241

    Article  CAS  PubMed  Google Scholar 

  54. Samama P, Cotecchia S, Costa T, Lefkowitz RJ (1993) A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem 268(7):4625–4636

    CAS  PubMed  Google Scholar 

  55. Gether U, Lin S, Kobilka BK (1995) Fluorescent labeling of purified beta 2 adrenergic receptor. Evidence for ligand-specific conformational changes. J Biol Chem 270(47):28268–28275

    Article  CAS  PubMed  Google Scholar 

  56. Cordeaux Y, Ijzerman AP, Hill SJ (2004) Coupling of the human A1 adenosine receptor to different heterotrimeric G proteins: evidence for agonist-specific G protein activation. Br J Pharmacol 143(6):705–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH/NIDDK RO1 DK095879 to Dr. Hering-Smith.

Funding

This study was funded by NIH/NIDDK RO1 DK095879 to Dr. Hering-Smith. Dr. Hering-Smith is also supported by the NIH Louisiana Clinical and Translational Sciences Center (LA CaTS) grant.

Author information

Authors and Affiliations

  1. Nephrology and Hypertension 8545, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA

    Ryan W. Walker, Shijia Zhang, Joycelynn A. Coleman-Barnett, L. Lee Hamm & Kathleen S. Hering-Smith

Authors
  1. Ryan W. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shijia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joycelynn A. Coleman-Barnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Lee Hamm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathleen S. Hering-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen S. Hering-Smith.

Ethics declarations

Conflict of interest

Dr. Ryan Walker declares that he has no conflict of interest. Dr. Shijia Zhang declares that he has no conflict of interest. Ms. Joycelynn Coleman-Barnett declares that she has no conflict of interest. Dr. L. Lee Hamm declares that he has no conflict of interest. Dr. Kathleen Hering-Smith declares that she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Walker, R.W., Zhang, S., Coleman-Barnett, J.A. et al. Calcium receptor signaling and citrate transport. Urolithiasis 46, 409–418 (2018). https://doi.org/10.1007/s00240-018-1035-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00240-018-1035-0

Keywords

Search

Navigation