Skip to main content
Log in

Non-specific effects of calcium entry antagonists in mast cells

  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

Calcium entry in non-excitable cells occurs through calcium-selective currents activated secondarily to store depletion and/or through non-selective cation channels (e.g., receptor- or second-messenger-activated channels). The driving force for calcium influx can be modified by chloride or potassium channels, which set the membrane potential of cells. Together, these conductances determine the extent of calcium entry. Mast cells are an excellent model system for studying calcium influx, because calcium-release-activated calcium currents (I CRAC), second-messenger-activated non-selective currents and chloride currents are present in these cells. Whole-cell patch-clamp recordings were used to test the Effects of the commonly used calcium entry blockers econazole and SK&F 96365, as well as the antiallergic and anti-inflammatory drugs tenidap, ketotifen and cromolyn on these channels. All tested drugs blocked the three different channel types with a similar order of magnitude (IC50 values ranging from micromolar to millimolar). Hence, these drugs cannot be used to discriminate between different calcium entry mechanisms.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alvarez J, Montero M, Garcia SJ (1992) Cytochrome P450 may regulate plasma membrane Ca2+ permeability according to the filling state of the intracellular Ca2+ stores. FASEB J 6:786–792

    Google Scholar 

  2. Alvarez J, Montero M, Garcia SJ (1992) High affinity inhibi-tion of Ca2+-dependent K+ channels by cytochrome P-450 inhibitors. J Biol Chem 267:11 789–11 793

    Google Scholar 

  3. Cleveland PL, Millard PJ, Showell HJ, Fewtrell CM (1993) Tenidap: a novel inhibitor of calcium influx in a mast cell line. Cell Calcium 14:1–16

    Google Scholar 

  4. Fasolato C, Hoth M, Matthews G, Penner R (1993) Ca2+ and Mn2+ influx through receptor-mediated activation of nonspecific cation channels in mast cells. Proc Natl Acad Sci USA 90:3068–3072

    Google Scholar 

  5. Fasolato C, Hoth M, Penner R (1993) A GTP-dependent step in the activation mechanism of capacitative calcium influx. J Biol Chem 268:20 737–20 740

    Google Scholar 

  6. Fasolato C, Innocenti B, Pozzan T (1994) Receptor-activated Ca2+ influx: how many mechanism for how many channels? Trends Pharmacol Sci 15:77–83

    Google Scholar 

  7. Hanada S, Oga S (1991) Histamine release from rat mast cells induced by econazole. Gen Pharmacol 22:511–513

    Google Scholar 

  8. Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356

    Google Scholar 

  9. Hoth M, Penner R (1993) Calcium release-activated calcium current in rat mast cells. J Physiol (Lond) 465:359–386

    Google Scholar 

  10. Krautwurst D, Hescheler J, Arndts D, Losel W, Hammer R, Schultz G (1993) Novel potent inhibitor of receptor-activated nonselective cation currents in HL-60 cells. Mol Pharmacol 43:655–659

    Google Scholar 

  11. Kuriyama K, Hiyama Y, Ito K, Yoshinaka I, Bito Y (1988) The protective effect of a new antiallergic agent, KP-136 on mast cell activation: a comparison with disodium cromoglycate. Agents Actions 25:321–325

    Google Scholar 

  12. Martin U, Römer D (1978) The pharmacological properties of a new, orally active antianaphylactic compound: ketotifen, a bezocycloheptathiophene. Arzneimittelforschung 28:770–782

    Google Scholar 

  13. Matthews G, Neher E, Penner R (1989) Chloride conductance activated by external agonists and internal messengers in rat peritoneal mast cells. J Physiol (Lond) 418:131–144

    Google Scholar 

  14. Matthews G, Neher E, Penner R (1989) Second messenger-activated calcium influx in rat peritoneal mast cells. J Physiol (Lond) 418:105–130

    Google Scholar 

  15. Mazurek N, Bashkin P, Petrank A, Pecht I (1983) Basophil variants with impaired cromoglycate binding do not respond to an immunological degranulation stimulus. Nature 303:528–530

    Google Scholar 

  16. McDonald TV, Premack BA, Gardner P (1993) Flash photolysis of caged ionositol 1,4,5-trisphosphate activates plasma membrane calcium current in human T cells. J Biol Chem 268:3889–3896

    Google Scholar 

  17. Merritt JE, Armstrong WP, Benham CD, Hallam TJ, Jacob R, Jaxa CA, Leigh BK, McCarthy SA, Moores KE, Rink TJ (1990) SK&F 96365, a novel inhibitor of receptor-mediated calcium entry. Biochem J 271:515–522

    Google Scholar 

  18. Metzger H, Alcarez G, Hohman R, Kinet JP, Pribluda V, Quarto R (1986) The receptor with high affinity for immuno-globulin E. Annu Rev Immunol 4:419–470

    Google Scholar 

  19. Middleton EJ, Ferriola P, Drzewiecki G, Sofia RD (1989) The effect of azelastine and some other antiasthmatic and antiallergic drugs on calmodulin and protein kinase C. Agents Actions 28:9–15

    Google Scholar 

  20. Okayama Y, Church MK (1992) Comparison of the modulatory effect of ketotifen, sodium cromoglycate, procaterol and salbutamol in human skin, lung and tonsil mast cells. Int Arch Allergy Immunol 97:216–225

    Google Scholar 

  21. Parekh AB, Terlau H, Stuhmer W (1993) Depletion of InsP3 stores activates a Ca2+ and K+ current by means of a phosphatase and a diffusible messenger. Nature 364:814–818

    Google Scholar 

  22. Penner R, Fasolato C, Hoth M (1993) Calcium influx and its control by calcium release. Curr Opin Neurobiol 3:368–374

    Google Scholar 

  23. Putney JJ (1990) Capacitative calcium entry revisited. Cell Calcium 11:611–624

    Google Scholar 

  24. Reinsprecht M, Pecht I, Schindler H, Romanin C (1992) Potent block of Cl channels by antiallergic drags. Biochem Biophys Res Commun 188:957–963

    Google Scholar 

  25. Rodrigues AD, Gibson GG, Ioannides C, Parke DV (1987) Interactions of imidazole antifungal agents with purified cytochrome P-450 proteins. Biochem Pharmacol 36:4277–4281

    Google Scholar 

  26. Sargeant P, Clarkson WD, Sage SO, Heemskerk JW (1992) Calcium influx evoked by Ca2+ store depletion in human platelets is more susceptible to cytochrome P-450 inhibitors than receptor-mediated calcium entry. Cell Calcium 13:553–564

    Google Scholar 

  27. Schwarz G, Droogmans G, Nilius B (1994) Multiple effects of SK&F 96365 on ionic currents and intracellular calcium in human endothelial cells. Cell Calcium 15:45–54

    Google Scholar 

  28. Sydbom A (1988) Characteristics of β-endorphin-induced histamine release from rat serosal mast cells. Comparison with neurotensin, dynorphin and compound 48/80. Naunyn Schmiedebergs Arch Pharmacol 338:567–572

    Google Scholar 

  29. Truneh A, White JR, Pearce FL (1982) Effect of ketotifen and oxatomide on histamine secretion from mast cells. Agents Actions 12:206–209

    Google Scholar 

  30. Villalobos C, Fonteriz R, Lopez MG, Garcia AG, Garcia SJ (1992) Inhibition of voltage-gated Ca2+ entry into GH3 and chromaffin cells by imidazole antimycotics and other cytochrome P450 blockers. FASEB J 6:2742–2747

    Google Scholar 

  31. Zweifach A, Lewis RS (1993) Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc Natl Acad Sci USA 90:6295–6299

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Franzius, D., Hoth, M. & Penner, R. Non-specific effects of calcium entry antagonists in mast cells. Pflugers Arch. 428, 433–438 (1994). https://doi.org/10.1007/BF00374562

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00374562

Key words

Navigation