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J. Biol. Chem., Vol. 283, Issue 31, 21418-21426, August 1, 2008

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Capsaicin Stimulates Uncoupled ATP Hydrolysis by the Sarcoplasmic Reticulum Calcium Pump^*

From the Institute of Physiology and Biophysics, University of Aarhus, DK-8000 Aarhus C, Denmark

In muscle cells the sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA) couples the free energy of ATP hydrolysis to pump Ca²⁺ ions from the cytoplasm to the SR lumen. In addition, SERCA plays a key role in non-shivering thermogenesis through uncoupled reactions, where ATP hydrolysis takes place without active Ca²⁺ translocation. Capsaicin (CPS) is a naturally occurring vanilloid, the consumption of which is linked with increased metabolic rate and core body temperature. Here we document the stimulation by CPS of the Ca²⁺-dependent ATP hydrolysis by SERCA without effects on Ca²⁺ accumulation. The stimulation by CPS was significantly dependent on the presence of a Ca²⁺ gradient across the SR membrane. ATP activation assays showed that the drug reduced the nucleotide affinity at the catalytic site, whereas the affinity at the regulatory site increased. Several biochemical analyses indicated that CPS stabilizes an ADP-insensitive E₂P-related conformation that dephosphorylates at a higher rate than the control enzyme. Under conditions where uncoupled SERCA was specifically inhibited by the treatment with fluoride, low temperatures, or dimethyl sulfoxide, CPS had no stimulatory effect on ATP hydrolysis by SERCA. It is concluded that CPS stabilizes a SERCA sub-conformation where Ca²⁺ is released from the phosphorylated intermediate to the cytoplasm instead of the SR lumen, increasing ATP hydrolysis not coupled with Ca²⁺ transport. To the best of our knowledge CPS is the first natural drug that augments uncoupled SERCA, presumably resulting in thermogenesis. The role of CPS as a SERCA modulator is discussed.

Received for publication, May 13, 2008 , and in revised form, June 2, 2008.

^* This study was supported by grants from Aarhus University Research Foundation, the Lundbeck Foundation, and the Novo Nordic Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Aarhus, Ole Worms Alle 1185, DK-8000 Aarhus C, Denmark. Tel.: 45-8942-2927; Fax: 45-8612-9599; E-mail: yam{at}biophys.au.dk.

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