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. 1986 Apr;49(4):795–801. doi: 10.1016/S0006-3495(86)83707-9

Effects of cyclosporine A on biomembranes. Vibrational spectroscopic, calorimetric and hemolysis studies.

T J O'Leary, P D Ross, M R Lieber, I W Levin
PMCID: PMC1329530  PMID: 3755063

Abstract

Cyclosporine A (CSA)-dipalmitoylphosphatidylcholine (DPPC) interactions were investigated using scanning calorimetry, infrared spectroscopy, and Raman spectroscopy. CSA reduced both the temperature and the maximum heat capacity of the lipid bilayer gel-to-liquid crystalline phase transition; the relationship between the shift in transition temperature and CSA concentration indicates that the peptide does not partition ideally between DPPC gel and liquid crystalline phases. This nonideality can be accounted for by excluded volume interactions between peptide molecules. CSA exhibited a similar but much more pronounced effect on the pretransition; at concentrations of 1 mol % CSA the amplitude of the pretransition was less than 20% of its value in the pure lipid. Raman spectroscopy confirmed that the effects of CSA on the phase transitions are not accompanied by major structural alterations in either the lipid headgroup or acyl chain regions at temperatures away from the phase changes. Both infrared and Raman spectroscopic results demonstrated that CSA in the lipid bilayer exists largely in a beta-turn conformation, as expected from single crystal x-ray data; the lipid phase transition does not induce structural alterations in CSA. Although the polypeptide significantly affects DPPC model membrane bilayers, CSA neither inhibited hypotonic hemolysis nor caused erythrocyte hemolysis, in contrast to many chemical agents that are believed to act through membrane-mediated pathways. Thus, agents, such as CSA, that perturb phospholipid phase transitions do not necessarily cause functional changes in cell membranes.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bandekar J., Krimm S. Vibrational analysis of peptides, polypeptides, and proteins. VI. Assignment of beta-turn modes in insulin and other proteins. Biopolymers. 1980 Jan;19(1):31–36. doi: 10.1002/bip.1980.360190103. [DOI] [PubMed] [Google Scholar]
  2. Epand R. M., Sturtevant J. M. A calorimetric study of peptide-phospholipid interactions: the glucagon-dimyristoylphosphatidylcholine complex. Biochemistry. 1981 Aug 4;20(16):4603–4606. doi: 10.1021/bi00519a014. [DOI] [PubMed] [Google Scholar]
  3. Handschumacher R. E., Harding M. W., Rice J., Drugge R. J., Speicher D. W. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984 Nov 2;226(4674):544–547. doi: 10.1126/science.6238408. [DOI] [PubMed] [Google Scholar]
  4. Hill M. W. Interaction of lipid vesicles with anesthetics. Ann N Y Acad Sci. 1978;308:101–110. doi: 10.1111/j.1749-6632.1978.tb22016.x. [DOI] [PubMed] [Google Scholar]
  5. Krimm S., Bandekar J. Vibrational analysis of peptides, polypeptides, and proteins. V. Normal vibrations of beta-turns. Biopolymers. 1980 Jan;19(1):1–29. doi: 10.1002/bip.1980.360190102. [DOI] [PubMed] [Google Scholar]
  6. Lavialle F., Adams R. G., Levin I. W. Infrared spectroscopic study of the secondary structure of melittin in water, 2-chloroethanol, and phospholipid bilayer dispersions. Biochemistry. 1982 May 11;21(10):2305–2312. doi: 10.1021/bi00539a006. [DOI] [PubMed] [Google Scholar]
  7. LeGrue S. J., Friedman A. W., Kahan B. D. Binding of cyclosporine by human lymphocytes and phospholipid vesicles. J Immunol. 1983 Aug;131(2):712–718. [PubMed] [Google Scholar]
  8. Lookman T., Pink D. A., Grundke E. W., Zuckermann M. J., deVerteuil F. Phase separation in lipid bilayers containing integral proteins. Computer simulation studies. Biochemistry. 1982 Oct 26;21(22):5593–5601. doi: 10.1021/bi00265a032. [DOI] [PubMed] [Google Scholar]
  9. Mabrey S., Mateo P. L., Sturtevant J. M. High-sensitivity scanning calorimetric study of mixtures of cholesterol with dimyristoyl- and dipalmitoylphosphatidylcholines. Biochemistry. 1978 Jun 13;17(12):2464–2468. doi: 10.1021/bi00605a034. [DOI] [PubMed] [Google Scholar]
  10. Marcelja S. Lipid-mediated protein interaction in membranes. Biochim Biophys Acta. 1976 Nov 11;455(1):1–7. doi: 10.1016/0005-2736(76)90149-8. [DOI] [PubMed] [Google Scholar]
  11. Merion R. M., White D. J., Thiru S., Evans D. B., Calne R. Y. Cyclosporine: five years' experience in cadaveric renal transplantation. N Engl J Med. 1984 Jan 19;310(3):148–154. doi: 10.1056/NEJM198401193100303. [DOI] [PubMed] [Google Scholar]
  12. Mountcastle D. B., Biltonen R. L., Halsey M. J. Effect of anesthetics and pressure on the thermotropic behavior of multilamellar dipalmitoylphosphatidylcholine liposomes. Proc Natl Acad Sci U S A. 1978 Oct;75(10):4906–4910. doi: 10.1073/pnas.75.10.4906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. O'Leary T. J., Ross P. D., Levin I. W. Effects of anesthetic and nonanesthetic steroids on dipalmitoylphosphatidylcholine liposomes: a calorimetric and Raman spectroscopic investigation. Biochemistry. 1984 Sep 25;23(20):4636–4641. doi: 10.1021/bi00315a019. [DOI] [PubMed] [Google Scholar]
  14. Owicki J. C., Springgate M. W., McConnell H. M. Theoretical study of protein--lipid interactions in bilayer membranes. Proc Natl Acad Sci U S A. 1978 Apr;75(4):1616–1619. doi: 10.1073/pnas.75.4.1616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pearson L. T., Edelman J., Chan S. I. Statistical mechanics of lipid membranes. Protein correlation functions and lipid ordering. Biophys J. 1984 May;45(5):863–871. doi: 10.1016/S0006-3495(84)84232-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Petcher T. J., Weber H., Rüegger A. Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A. Helv Chim Acta. 1976 Jun 14;59(5):1480–1489. doi: 10.1002/hlca.19760590509. [DOI] [PubMed] [Google Scholar]
  17. Pink D. A., Chapman D. Protein-lipid interactions in bilayer membranes: a lattice model. Proc Natl Acad Sci U S A. 1979 Apr;76(4):1542–1546. doi: 10.1073/pnas.76.4.1542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ryffel B., Götz U., Heuberger B. Cyclosporin receptors on human lymphocytes. J Immunol. 1982 Nov;129(5):1978–1982. [PubMed] [Google Scholar]
  19. Scott H. L., Cheng W. H. A theoretical model for lipid mixtures, phase transitions, and phase diagrams. Biophys J. 1979 Oct;28(1):117–132. doi: 10.1016/S0006-3495(79)85163-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Scott H. L., Jr, Coe T. J. A theoretical study of lipid-protein interactions in bilayers. Biophys J. 1983 Jun;42(3):219–224. doi: 10.1016/S0006-3495(83)84389-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Seeman P. The membrane actions of anesthetics and tranquilizers. Pharmacol Rev. 1972 Dec;24(4):583–655. [PubMed] [Google Scholar]
  22. Sturtevant J. M. A scanning calorimetric study of small molecule-lipid bilayer mixtures. Proc Natl Acad Sci U S A. 1982 Jul;79(13):3963–3967. doi: 10.1073/pnas.79.13.3963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Susi H., Sampugna J., Hampson J. W., Ard J. S. Laser-Raman investigation of phospholipid-polypeptide interactions in model membranes. Biochemistry. 1979 Jan 23;18(2):297–301. doi: 10.1021/bi00569a010. [DOI] [PubMed] [Google Scholar]
  24. Yeagle P. L. 31P nuclear magnetic resonance studies of the phospholipid-protein interface in cell membranes. Biophys J. 1982 Jan;37(1):227–239. doi: 10.1016/S0006-3495(82)84672-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

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