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. 1991 Feb 15;274(Pt 1):193–197. doi: 10.1042/bj2740193

Cytochrome P-450 may link intracellular Ca2+ stores with plasma membrane Ca2+ influx.

J Alvarez 1, M Montero 1, J García-Sancho 1
PMCID: PMC1149938  PMID: 2001232

Abstract

We have studied the mechanism of the regulation of plasma membrane Ca2+ permeability by the degree of filling of the intracellular Ca2+ stores. Using Mn2+ as a Ca2+ surrogate for plasma membrane Ca2+ channels, we found that Mn2+ uptake by rat thymocytes is inversely related to the degree of filling of the intracellular Ca2+ stores. This store-dependent plasma membrane permeability is inhibited by oxygen scavenging, CO, imidazole antimycotics and other cytochrome P-450 inhibitors. The pattern of inhibition is similar to that reported previously for the inhibition of microsomal cytochrome P-450-mediated aryl hydrocarbon hydroxylase activity of lymphocytes. Several calmodulin antagonists, both phenothiazinic (trifluoperazine, fluphenazine and chlorpromazine) and dibenzodiazepinic (clozapine), accelerate Mn2+ uptake by cells with Ca2(+)-filled stores, and this effect is prevented by imidazole antimycotics. Our results suggest that cytochrome P-450 may be the link between the stores and the plasma membrane Ca2+ pathway. We propose a model in which this cytochrome, sited at the stores, stimulates plasma membrane Ca2+ influx. This stimulatory effect is, in turn, prevented by the presence of Ca2+ inside the stores, possibly via a calmodulin-dependent mechanism.

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Selected References

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

  1. Ahokas J. T., Davies C., Jacobsen N., Kärki N. T., Philippides A., Treston A. M. The metabolism of 2,5-diphenyloxazole (PPO) in human lymphocytes and rat liver microsomes. Pharmacol Toxicol. 1987 Sep;61(3):184–190. doi: 10.1111/j.1600-0773.1987.tb01800.x. [DOI] [PubMed] [Google Scholar]
  2. Alonso M. T., Sanchez A., García-Sancho J. Monitoring of the activation of receptor-operated calcium channels in human platelets. Biochem Biophys Res Commun. 1989 Jul 14;162(1):24–29. doi: 10.1016/0006-291x(89)91956-6. [DOI] [PubMed] [Google Scholar]
  3. Alvarez J., García-Sancho J., Herreros B. The role of calmodulin on Ca2+ -dependent K+ transport regulation in the human red cell. Biochim Biophys Acta. 1986 Aug 7;860(1):25–34. doi: 10.1016/0005-2736(86)90494-3. [DOI] [PubMed] [Google Scholar]
  4. Amsbaugh S. C., Ding J. H., Swan D. C., Popescu N. C., Chen Y. T. Expression and chromosomal localization of the cytochrome P1-450 gene in human mitogen-stimulated lymphocytes. Cancer Res. 1986 May;46(5):2423–2427. [PubMed] [Google Scholar]
  5. Artalejo A. R., García-Sancho J. Mobilization of intracellular calcium by extracellular ATP and by calcium ionophores in the Ehrlich ascites-tumour cell. Biochim Biophys Acta. 1988 Jun 7;941(1):48–54. doi: 10.1016/0005-2736(88)90212-x. [DOI] [PubMed] [Google Scholar]
  6. Ayub M., Levell M. J. Structure-activity relationships of the inhibition of human placental aromatase by imidazole drugs including ketoconazole. J Steroid Biochem. 1988 Jul;31(1):65–72. doi: 10.1016/0022-4731(88)90207-5. [DOI] [PubMed] [Google Scholar]
  7. Baran D. T., Peck W. A., Frengley P. A., Lichtman M. A. Cortisol-induced inhibition of amino acid transport in thymic lymphocytes: kinetic parameters; relation to ATP levels and protein synthesis; and specificity. Biochim Biophys Acta. 1973 May 25;307(3):627–639. doi: 10.1016/0005-2736(73)90307-6. [DOI] [PubMed] [Google Scholar]
  8. Capdevila J., Gil L., Orellana M., Marnett L. J., Mason J. I., Yadagiri P., Falck J. R. Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism. Arch Biochem Biophys. 1988 Mar;261(2):257–263. doi: 10.1016/0003-9861(88)90340-2. [DOI] [PubMed] [Google Scholar]
  9. Crouch M. F., Lapetina E. G. No direct correlation between Ca2+ mobilization and dissociation of Gi during platelet phospholipase A2 activation. Biochem Biophys Res Commun. 1988 May 31;153(1):21–30. doi: 10.1016/s0006-291x(88)81184-7. [DOI] [PubMed] [Google Scholar]
  10. Erickson R. R., Prasad J. S., Holtzman J. L. The role of NADPH- and reduced glutathione-dependent enzymes in the norepinephrine modulation of the ATP-dependent, hepatic microsomal calcium pump: a new pathway for the noradrenergic regulation of cytosolic calcium in the hepatocyte. J Pharmacol Exp Ther. 1987 Aug;242(2):472–477. [PubMed] [Google Scholar]
  11. Exton J. H. Mechanisms of action of calcium-mobilizing agonists: some variations on a young theme. FASEB J. 1988 Aug;2(11):2670–2676. doi: 10.1096/fasebj.2.11.2456243. [DOI] [PubMed] [Google Scholar]
  12. Garcia-Sancho J., Alonso M. T., Sanchez A. Receptor-operated calcium channels in human platelets. Biochem Soc Trans. 1989 Dec;17(6):980–982. doi: 10.1042/bst0170980. [DOI] [PubMed] [Google Scholar]
  13. Gietzen K., Adamczyk-Engelmann P., Wüthrich A., Konstantinova A., Bader H. Compound 48/80 is a selective and powerful inhibitor of calmodulin-regulated functions. Biochim Biophys Acta. 1983 Dec 7;736(1):109–118. doi: 10.1016/0005-2736(83)90175-x. [DOI] [PubMed] [Google Scholar]
  14. Goldyne M. E. Lymphocytes and arachidonic acid metabolism. Prog Allergy. 1988;44:140–152. [PubMed] [Google Scholar]
  15. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  16. Jacob R. Agonist-stimulated divalent cation entry into single cultured human umbilical vein endothelial cells. J Physiol. 1990 Feb;421:55–77. doi: 10.1113/jphysiol.1990.sp017933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Means A. R., Dedman J. R. Calmodulin--an intracellular calcium receptor. Nature. 1980 May 8;285(5760):73–77. doi: 10.1038/285073a0. [DOI] [PubMed] [Google Scholar]
  18. Montero M., Alvarez J., Garcia-Sancho J. Uptake of Ca2+ and refilling of intracellular Ca2+ stores in Ehrlich-ascites-tumour cells and in rat thymocytes. Biochem J. 1990 Oct 15;271(2):535–540. doi: 10.1042/bj2710535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Negishi M., Nebert D. W. Structural gene products of the Ah locus. Genetic and immunochemical evidence for two forms of mouse liver cytochrome P-450 induced by 3-methylcholanthrene. J Biol Chem. 1979 Nov 10;254(21):11015–11023. [PubMed] [Google Scholar]
  20. Ohnishi T., Wada A., Nonaka Y., Sugiyama T., Yamano T., Okamoto M. Effect of calmodulin on aldosterone synthesis by a cytochrome P-45011 beta-reconstituted system from bovine adrenocortical mitochondria. J Biochem. 1986 Oct;100(4):1065–1076. doi: 10.1093/oxfordjournals.jbchem.a121786. [DOI] [PubMed] [Google Scholar]
  21. Pandol S. J., Schoeffield M. S., Fimmel C. J., Muallem S. The agonist-sensitive calcium pool in the pancreatic acinar cell. Activation of plasma membrane Ca2+ influx mechanism. J Biol Chem. 1987 Dec 15;262(35):16963–16968. [PubMed] [Google Scholar]
  22. Rao G. H. Influence of calmodulin antagonist (stelazine) on agonist-induced calcium mobilization and platelet activation. Biochem Biophys Res Commun. 1987 Oct 29;148(2):768–775. doi: 10.1016/0006-291x(87)90942-9. [DOI] [PubMed] [Google Scholar]
  23. Rodrigues A. D., Gibson G. G., Ioannides C., Parke D. V. Interactions of imidazole antifungal agents with purified cytochrome P-450 proteins. Biochem Pharmacol. 1987 Dec 15;36(24):4277–4281. doi: 10.1016/0006-2952(87)90670-8. [DOI] [PubMed] [Google Scholar]
  24. Sage S. O., Pintado E., Mahaut-Smith M. P., Merritt J. E. Rapid kinetics of agonist-evoked changes in cytosolic free Ca2+ concentration in fura-2-loaded human neutrophils. Biochem J. 1990 Feb 1;265(3):915–918. doi: 10.1042/bj2650915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sage S. O., Reast R., Rink T. J. ADP evokes biphasic Ca2+ influx in fura-2-loaded human platelets. Evidence for Ca2+ entry regulated by the intracellular Ca2+ store. Biochem J. 1990 Feb 1;265(3):675–680. doi: 10.1042/bj2650675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sanchez A., Alonso M. T., Collazos J. M. Thrombin-induced changes of intracellular [Ca2+] and pH in human platelets. Cytoplasmic alkalinization is not a prerequisite for calcium mobilization. Biochim Biophys Acta. 1988 Mar 3;938(3):497–500. doi: 10.1016/0005-2736(88)90149-6. [DOI] [PubMed] [Google Scholar]
  27. Sekiya K., Okuda H. Selective inhibition of platelet lipoxygenase by baicalein. Biochem Biophys Res Commun. 1982 Apr 14;105(3):1090–1095. doi: 10.1016/0006-291x(82)91081-6. [DOI] [PubMed] [Google Scholar]
  28. Song B. J., Gelboin H. V., Park S. S., Tsokos G. C., Friedman F. K. Monoclonal antibody-directed radioimmunoassay detects cytochrome P-450 in human placenta and lymphocytes. Science. 1985 Apr 26;228(4698):490–492. doi: 10.1126/science.2580351. [DOI] [PubMed] [Google Scholar]
  29. Sáez J. C., Bennett M. V., Spray D. C. Carbon tetrachloride at hepatotoxic levels blocks reversibly gap junctions between rat hepatocytes. Science. 1987 May 22;236(4804):967–969. doi: 10.1126/science.3576214. [DOI] [PubMed] [Google Scholar]
  30. Takemura H., Hughes A. R., Thastrup O., Putney J. W., Jr Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells. Evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane. J Biol Chem. 1989 Jul 25;264(21):12266–12271. [PubMed] [Google Scholar]
  31. Takemura H., Putney J. W., Jr Capacitative calcium entry in parotid acinar cells. Biochem J. 1989 Mar 1;258(2):409–412. doi: 10.1042/bj2580409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weiss B., Levin R. M. Mechanism for selectively inhibiting the activation of cyclic nucleotide phosphodiesterase and adenylate cyclase by antipsychotic agents. Adv Cyclic Nucleotide Res. 1978;9:285–303. [PubMed] [Google Scholar]
  33. Whitlock J. P., Jr, Cooper H. L., Gelboin V. H. Aryl hydrocarbon (benzopyrene) hydroxylase is stimulated in human lymphocytes by mitogens and benz(a)anthracene. Science. 1972 Aug 18;177(4049):618–619. doi: 10.1126/science.177.4049.618. [DOI] [PubMed] [Google Scholar]
  34. Williams D. A., Fogarty K. E., Tsien R. Y., Fay F. S. Calcium gradients in single smooth muscle cells revealed by the digital imaging microscope using Fura-2. Nature. 1985 Dec 12;318(6046):558–561. doi: 10.1038/318558a0. [DOI] [PubMed] [Google Scholar]
  35. Williamson J. R., Monck J. R. Hormone effects on cellular Ca2+ fluxes. Annu Rev Physiol. 1989;51:107–124. doi: 10.1146/annurev.ph.51.030189.000543. [DOI] [PubMed] [Google Scholar]

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