Clotrimazole inhibits the Ca2+-ATPase (SERCA) by interfering with Ca2+ binding and favoring the E2 conformation

doi:10.1074/jbc.M510550200

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Papers In Press, published online ahead of print February 1, 2006
J. Biol. Chem, 10.1074/jbc.M510550200
Submitted on September 27, 2005
Accepted on February 1, 2006

Clotrimazole inhibits the Ca²+-ATPase (SERCA) by interfering with Ca²+ binding and favoring the E2 conformation

Gianluca Bartolommei, Francesco Tadini-Buoninsegni, Suming Hua, Maria Rosa Moncelli, Giuseppe Inesi, and Rolando Guidelli

Dept. of Chemistry, University of Florence, Sesto Fiorentino, Florence 50019

Corresponding Author: guidelli{at}unifi.it

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 SR 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 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 P_i 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 conformational effects of the activating cation.

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