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.
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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
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
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
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
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
Fasolato C, Innocenti B, Pozzan T (1994) Receptor-activated Ca2+ influx: how many mechanism for how many channels? Trends Pharmacol Sci 15:77–83
Hanada S, Oga S (1991) Histamine release from rat mast cells induced by econazole. Gen Pharmacol 22:511–513
Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356
Hoth M, Penner R (1993) Calcium release-activated calcium current in rat mast cells. J Physiol (Lond) 465:359–386
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
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
Martin U, Römer D (1978) The pharmacological properties of a new, orally active antianaphylactic compound: ketotifen, a bezocycloheptathiophene. Arzneimittelforschung 28:770–782
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
Matthews G, Neher E, Penner R (1989) Second messenger-activated calcium influx in rat peritoneal mast cells. J Physiol (Lond) 418:105–130
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
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
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
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
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
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
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
Penner R, Fasolato C, Hoth M (1993) Calcium influx and its control by calcium release. Curr Opin Neurobiol 3:368–374
Putney JJ (1990) Capacitative calcium entry revisited. Cell Calcium 11:611–624
Reinsprecht M, Pecht I, Schindler H, Romanin C (1992) Potent block of Cl− channels by antiallergic drags. Biochem Biophys Res Commun 188:957–963
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
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
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
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
Truneh A, White JR, Pearce FL (1982) Effect of ketotifen and oxatomide on histamine secretion from mast cells. Agents Actions 12:206–209
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
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
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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
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DOI: https://doi.org/10.1007/BF00374562