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Extracellular site for econazole‐mediated block of Ca 2+ release‐activated Ca 2+ current ( I crac ) in T lymphocytes
Author(s) -
Christian Edward P.,
Spence Katherine T.,
Togo James A.,
Dargis Pauline G.,
Warawa Edward
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15722.x
Subject(s) - econazole , extracellular , chemistry , biophysics , biochemistry , biology , miconazole , antifungal , microbiology and biotechnology
1 Standard whole cell patch clamp recording techniques were used to study the pharmacological characteristics and site of econazole‐mediated inhibition of calcium release‐activated calcium current ( I crac ) in the human leukaemic T cell line, Jurkat. 2 Extracellularly applied econazole blocked I crac in a concentration‐dependent manner (IC 50 ≅ 14 μ m ). Block developed over a relatively slow timecourse of 30–60 s (10 μ m ), and only partially reversed over minutes. 3 Econazole dialysed from the pipette into the cytosol at concentrations ranging from 0.1 to 30 μ m did not reduce I crac , or quantitatively affect I crac block by extracellularly applied econazole. 4 A less lipophilic quaternary iodide derivative of econazole was synthesized to retard absorption through the cell membrane. When applied extracellularly, this compound blocked I crac in a concentration‐dependent manner with onset kinetics comparable to econazole. 5 Results with intracellularly dialysed econazole and the quaternary econazole derivative provide convergent evidence that econazole blocks I crac via an extracellular interaction. 6 The inability of intracellularly applied econazole to inhibit I crac argues against the notion that econazole inhibits capacitative Ca 2+ entry pathways secondary to its known inhibitory effects on cytochrome P‐450.