Econazole  depleted  calcium  release-activated  calcium  (CRAC)  current  through  blockade  of  voltage-dependent Ca 2+  channels

Agung Endro Nugroho; Hari Purnomo; Kazutaka Maeyama

doi:10.14499/indonesianjpharm0iss0pp128-136

Econazole depleted calcium release-activated calcium (CRAC) current through blockade of voltage-dependent Ca 2+ channels

Agung Endro Nugroho, Hari Purnomo, Kazutaka Maeyama

Abstract

Econazole is an azole antifungal agent which can block the calcium release-activated calcium (CRAC) current in human leukaemic T cell line. The phenomenon is also possible to occur in mast cell such as RBL-2H3 (rat basophilic leukemia) cells, a tumor analog of mast cells. In the study, we investigated effect of econazole on ⁴⁵Ca²⁺ uptake into the cells in response to thapsigargin, an ATP-dependent Ca²⁺ (SERCA) inhibitor, by direct measurement of radiolabelled Ca²⁺ uptake in cells. The mechanism underlying this effect of econazole was studied using molecular modelling. In present study, econazole inhibited ⁴⁵Ca²⁺ influx into mast cells in absence of mast cells inducer, thapsigargin. Moreover, econazole potently suppressed the ⁴⁵Ca²⁺ influx induced by thapsigargin. It was supported that econazole also inhibited Ca^2+-induced tracheal contraction. The increase of Ca²⁺ was stimulated by the opening of voltage-dependent Ca²⁺ channels activated by KCl-induced membrane depolarization. Based on molecular docking study, score of interaction (equal to energy of interaction) of 3FGO, a main protein target on Ca²⁺ -ATPase, with native ligan, thapsigargin and econazole were -76.941, -117.205, and -92.277, respectively. The interaction of thapsigargin and Ca²⁺ -ATPase was more stable than this of econazole and Ca²⁺ -ATPase. It suggests that it would be difficult for econazole to block the interaction of thapsigargin with Ca²⁺ -ATPase to increase intracellular Ca²⁺.In conclusion, econazole inhibited the increase of intracellular Ca2+involving the blokade of voltage-dependent Ca²⁺ channels, but not involving the Ca²⁺ -ATPase pathway.

Key words :econazole, Ca²⁺ -ATPase, CRAC current, thapsigargin

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DOI: http://dx.doi.org/10.14499/indonesianjpharm0iss0pp128-136