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. 1976 Mar;57(3):559–568. doi: 10.1172/JCI108311

Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3',5'-monophosphate excretion.

L R Forte, G A Nickols, C S Anast
PMCID: PMC436688  PMID: 175088

Abstract

This study examined the role of cyclic AMP in the phosphaturic response to parathyroid hormone in vitamin D-deficient rats. Infusion of purified bovine parathyroid hormone (13.3 mug/h) into control, D-fed, or D-deficient, thyroparathyroidectomized rats produced a sixfold increase in renal phosphate and cyclic AMP excretion in D-fed rats, but only a two- to threefold increase in both parameters in D-deficient animals. Intravenous injection of parathyroid hormone over the dosage range from 1-50 mug/kg resulted in a dose-dependent increase in phosphate and cyclic AMP excretion with both D-fed and D-deficient thyroparathyroidectomized rats. However, the D-deficient rats responded to these injections of parathyroid hormone with a two- to threefold increase in both renal phosphate and cyclic AMP excretion at the highest dose of 50 mug/kg, whereas the D-fed animals' response was 35-fold and 11-fold over control excretion levels of phosphate and cyclic AMP, respectively. To directly examine the role of the renal cortical adenylate cyclase system in the blunted phosphaturic and urinary cyclic AMP responses to parathyroid hormone in D-deficient rats, we prepared a plasma membrane fraction enriched in this enzyme activity from the renal cortex of D-fed and D-deficient thyroparathyroidectomized rats. The renal cortical adenylate cyclase of D-deficient rats showed significantly (P less than 0.001) less activation by parathyroid hormone over the hormone concentration range from 0.3 to 7.0 mug/ml than was observed with the enzyme prepared from D-fed animals. Basal adenylate cyclase activity and the fluoride-stimulated enzyme activity were not altered by the state of D-deficiency. These experiments demonstrate that the blunted phosphaturic response to parathyroid hormone observed in D-deficient rats is associated with the reduced responsiveness of the renal cortical adenylate cyclase to the hormone. Moreover, the defect in the renal membrane adenylate cyclase system appears to be localized at the level of PTH binding to membrane receptors or, alternatively, at the level of transmission of the hormone-receptor binding signal to the catalytic moiety of this membrane enzyme.

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Selected References

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  1. Agus Z. S., Puschett J. B., Senesky D., Goldberg M. Mode of action of parathyroid hormone and cyclic adenosine 3',5'-monophosphate on renal tubular phosphate reabsorption in the dog. J Clin Invest. 1971 Mar;50(3):617–626. doi: 10.1172/JCI106532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arnaud C., Rasmussen H., Anast C. Further studies on the interrelationship between parathyroid hormone and vitamin D. J Clin Invest. 1966 Dec;45(12):1955–1964. doi: 10.1172/JCI105500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Au W. Y., Raisz L. G. Restoration of parathyroid responsiveness in vitamin D-deficient rats by parenteral calcium or dietary lactose. J Clin Invest. 1967 Oct;46(10):1572–1578. doi: 10.1172/JCI105648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bell N. H., Avery S., Sinha T., Clark C. M., Jr, Allen D. O., Johnston C., Jr Effects of dibutyryl cyclic adenosine 3',5'-monophosphate and parathyroid extract on calcium and phosphorus metabolism in hypoparathyroidism and pseudohypoparathyroidism. J Clin Invest. 1972 Apr;51(4):816–823. doi: 10.1172/JCI106876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. COTLOVE E. Simple tail vein infusion method for renal clearance measurements in the rat. J Appl Physiol. 1961 Jul;16:764–766. doi: 10.1152/jappl.1961.16.4.764. [DOI] [PubMed] [Google Scholar]
  6. Chase L. R., Aurbach G. D. Parathyroid function and the renal excretion of 3'5'-adenylic acid. Proc Natl Acad Sci U S A. 1967 Aug;58(2):518–525. doi: 10.1073/pnas.58.2.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chase L. R., Aurbach G. D. Renal adenyl cyclase: anatomically separate sites for parathyroid hormone and vasopressin. Science. 1968 Feb 2;159(3814):545–547. doi: 10.1126/science.159.3814.545. [DOI] [PubMed] [Google Scholar]
  8. Chase L. R., Aurbach G. D. The effect of parathyroid hormone on the concentration of adenosine 3',5'-monophosphate in skeletal tissue in vitro. J Biol Chem. 1970 Apr 10;245(7):1520–1526. [PubMed] [Google Scholar]
  9. Chase L. R., Fedak S. A., Aurbach G. D. Activation of skeletal adenyl cyclase by parathyroid hormone in vitro. Endocrinology. 1969 Apr;84(4):761–768. doi: 10.1210/endo-84-4-761. [DOI] [PubMed] [Google Scholar]
  10. Fitzpatrick D. F., Davenport G. R., Forte L., Landon E. J. Characterization of plasma membrane proteins in mammalian kidney. I. Preparation of a membrane fraction and separation of the protein. J Biol Chem. 1969 Jul 10;244(13):3561–3569. [PubMed] [Google Scholar]
  11. Forte L. R., Chao W. T., Walkenbach J., Byington K. H. Studies of kidney plasma membrane adenosine-3',5'-monophosphate-dependent protein kinase. Biochim Biophys Acta. 1975 Apr 21;389(1):84–96. doi: 10.1016/0005-2736(75)90387-9. [DOI] [PubMed] [Google Scholar]
  12. Forte L. R. Characterization of the adenyl cyclase of rat kidney plasma membranes. Biochim Biophys Acta. 1972 May 9;266(2):524–542. doi: 10.1016/0005-2736(72)90108-3. [DOI] [PubMed] [Google Scholar]
  13. Gavin J. R., 3rd, Roth J., Neville D. M., Jr, de Meyts P., Buell D. N. Insulin-dependent regulation of insulin receptor concentrations: a direct demonstration in cell culture. Proc Natl Acad Sci U S A. 1974 Jan;71(1):84–88. doi: 10.1073/pnas.71.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gilman A. G. A protein binding assay for adenosine 3':5'-cyclic monophosphate. Proc Natl Acad Sci U S A. 1970 Sep;67(1):305–312. doi: 10.1073/pnas.67.1.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. HARRISON H. C., HARRISON H. E., PARK E. A. Vitamin D and citrate metabolism; effect of vitamin D in rats fed diets adequate in both calcium and phosphorus. Am J Physiol. 1958 Feb;192(2):432–436. doi: 10.1152/ajplegacy.1958.192.2.432. [DOI] [PubMed] [Google Scholar]
  16. HARRISON H. E., HARRISON H. C. THE INTERACTION OF VITAMIN D AND PARATHYROID HORMONE ON CALCIUM PHOSPHORUS AND MAGNESIUM HOMEOSTASIS IN THE RAT. Metabolism. 1964 Oct;13:952–958. doi: 10.1016/0026-0495(64)90085-x. [DOI] [PubMed] [Google Scholar]
  17. Heersche J. N., Fedak S. A., Aurbach G. D. The mode of action of dibutyryl adenosine 3',5'-monophosphate on bone tissue in vitro. J Biol Chem. 1971 Nov 25;246(22):6770–6775. [PubMed] [Google Scholar]
  18. Kahn C. R., Neville D. M., Jr, Roth J. Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J Biol Chem. 1973 Jan 10;248(1):244–250. [PubMed] [Google Scholar]
  19. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  20. Miller J. P., Shuman D. A., Scholten M. B., Dimmitt M. K., Stewart C. M., Khwaja T. A., Robins R. K., Simon L. N. Synthesis and biological activity of some 2' derivatives of adenosine 3',5'-cyclic phosphate. Biochemistry. 1973 Feb 27;12(5):1010–1016. doi: 10.1021/bi00729a035. [DOI] [PubMed] [Google Scholar]
  21. Miyamoto E., Kuo J. F., Greengard P. Cyclic nucleotide-dependent protein kinases. 3. Purification and properties of adenosine 3',5'-monophosphate-dependent protein kinase from bovine brain. J Biol Chem. 1969 Dec 10;244(23):6395–6402. [PubMed] [Google Scholar]
  22. Morii H., DeLuca H. F. Relationship between vitamin D deficiency, thyrocalcitonin, and parathyroid hormone. Am J Physiol. 1967 Aug;213(2):358–362. doi: 10.1152/ajplegacy.1967.213.2.358. [DOI] [PubMed] [Google Scholar]
  23. Nagata N., Rasmussen H. Parathyroid hormone and renal cell metabolism. Biochemistry. 1968 Oct;7(10):3728–3733. doi: 10.1021/bi00850a053. [DOI] [PubMed] [Google Scholar]
  24. Nagata N., Rasmussen H. Parathyroid hormone, 3'5' AMP, Ca++, and renal gluconeogenesis. Proc Natl Acad Sci U S A. 1970 Feb;65(2):368–374. doi: 10.1073/pnas.65.2.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. RASMUSSEN H., DELUCA H., ARNAUD C., HAWKER C., VONSTEDINGK M. THE RELATIONSHIP BETWEEN VITAMIN D AND PARATHYROID HORMONE. J Clin Invest. 1963 Dec;42:1940–1946. doi: 10.1172/JCI104880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rasmussen H., Feinblatt J. The relationship between the actions of vitamin D, parathyroid hormone and calcitonin. Calcif Tissue Res. 1971;6(4):265–279. doi: 10.1007/BF02196208. [DOI] [PubMed] [Google Scholar]
  27. Rasmussen H., Pechet M., Fast D. Effect of dibutyryl cyclic adenosine 3',5'-monophosphate, theophylline, and other nucleotides upon calcium and phosphate metabolism. J Clin Invest. 1968 Aug;47(8):1843–1850. doi: 10.1172/JCI105874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rebhun L. I., Villar-Palasi C. Stimulation of purified muscle protein kinase by cyclic AMP and its butyrated derivatives. Biochim Biophys Acta. 1973 Sep 15;321(1):165–170. doi: 10.1016/0005-2744(73)90070-3. [DOI] [PubMed] [Google Scholar]
  29. STEENBOCK H., HERTING D. C. Vitamin D and growth. J Nutr. 1955 Dec 10;57(4):449–468. doi: 10.1093/jn/57.4.449. [DOI] [PubMed] [Google Scholar]
  30. White A. A., Zenser T. V. Separation of cyclic 3',5'-nucleoside monophosphates from other nucleotides on aluminum oxide columns. Application to the assay of adenyl cyclase and guanyl cyclase. Anal Biochem. 1971 Jun;41(2):372–396. doi: 10.1016/0003-2697(71)90156-4. [DOI] [PubMed] [Google Scholar]

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