Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 14, Pages 9547-9551Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M510550200
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- NHLBI NIH HHS [R01 HL69830] Funding Source: Medline
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Clotrimazole (CLT) is an antimycotic imidazole derivative that is known to inhibit cytochrome P-450, ergosterol biosynthesis and proliferation of cells in culture, and to interfere with cellular Ca2+ homeostasis. We found that CLT inhibits the Ca2+-ATPase of rabbit fast-twitch skeletal muscle (SERCA1), and we characterized in detail the effect of CLT on this calcium transport ATPase. We used biochemical methods for characterization of the ATPase and its partial reactions, and we also performed measurements of charge movements following adsorption of sarcoplasmic reticulum vesicles containing the ATPase onto a gold-supported biomimetic membrane. CLT inhibits Ca2+-ATPase and Ca2+ transport with a K-I of 35 mu M. Ca2+ binding in the absence of ATP and phosphoenzyme formation by the utilization of ATP in the presence of Ca2+ are also inhibited within the same CLT concentration range. On the other hand, phosphoenzyme formation by utilization of Pi in the absence of Ca2+ is only minimally inhibited. It is concluded that CLT inhibits primarily Ca2+ binding and, consequently, the Ca2+-dependent reactions of the SERCA cycle. It is suggested that CLT resides within the membrane-bound region of the transport ATPase, thereby interfering with binding and the conformational effects of the activating cation.
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