Cyclopiazonic acid inhibition of the Ca2+-transport ATPase in rat skeletal muscle sarcoplasmic reticulum vesicles

Goeger, Douglas E.; Riley, Ronald T.; Dorner, Joe W.; Cole, Richard

doi:10.1016/0006-2952(88)90195-5

Cited by 185 publications

(110 citation statements)

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“…1(A)) is an indole tetramic acid that functions as an inhibitor of sarcoplasmic or endoplasmic reticulum calcium-dependent ATPase (SERCA). 1,2) Some strains in the genera Aspergillus and Penicillium have been reported to produce CPA, 3) and the CPA derivatives 2-oxoCPA and speradine A (1-N-methyl-2-oxoCPA) ( Fig. 1(A)) are produced by Aspergillus oryzae NBRC 4177 4) and A. tamarii marine-derived isolate, 5) respectively.…”

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confidence: 99%

Cyclopiazonic acid biosynthesis gene cluster gene cpaM is required for speradine A biosynthesis

Tokuoka

Kikuchi

Shinohara

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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confidence: 99%

Cyclopiazonic acid biosynthesis gene cluster gene cpaM is required for speradine A biosynthesis

Tokuoka

Kikuchi

Shinohara

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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“…The crystal structures were essentially the same. Thus, only one conformation of the ATPase has been published so far for the E2 state.Cyclopiazonic acid (CPA) is another well known and potent inhibitor of SERCA1 (16,20). It binds to the ATPase in the E2 state and affects the enzymatic activity of Ca 2ϩ -ATPase in a way very similar to TG (21, 22).…”

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confidence: 99%

“…Several inhibitors specific to SERCA1 are available (15)(16)(17). By far the best known and most potent inhibitor is thapsigargin (TG), a plant sesquiterpene lactone (18), with the dissociation constant in the subnanomolar range (15).…”

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Interdomain communication in calcium pump as revealed in the crystal structures with transmembrane inhibitors

Takahashi

Kondou²,

Toyoshima³

2007

Proc. Natl. Acad. Sci. U.S.A.

110

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Ca 2؉ -ATPase of skeletal muscle sarcoplasmic reticulum is an ATPdriven Ca 2؉ pump consisting of three cytoplasmic domains and 10 transmembrane helices. In the absence of Ca 2؉ , the three cytoplasmic domains gather to form a compact headpiece, but the ATPase is unstable without an inhibitor. Here we describe the crystal structures of Ca 2؉ -ATPase in the absence of Ca 2؉ stabilized with cyclopiazonic acid alone and in combination with other inhibitors. Cyclopiazonic acid is located in the transmembrane region of the protein near the cytoplasmic surface. The binding site partially overlaps with that of 2,5-di-tert-butyl-1,4-dihydroxybenzene but is separate from that of thapsigargin. The overall structure is significantly different from that stabilized with thapsigargin: The cytoplasmic headpiece is more upright, and the transmembrane helices M1-M4 are rearranged. Cyclopiazonic acid primarily alters the position of the M1 helix and thereby M2 and M4 and then M5. Because M5 is integrated into the phosphorylation domain, the whole cytoplasmic headpiece moves. These structural changes show how an event in the transmembrane domain can be transmitted to the cytoplasmic domain despite flexible links between them. They also reveal that Ca 2؉ -ATPase has considerable plasticity even when fixed by a transmembrane inhibitor, presumably to accommodate thermal fluctuations.Ca 2ϩ -ATPase ͉ ion pump ͉ membrane protein C a 2ϩ -ATPase of skeletal muscle sarcoplasmic reticulum (SERCA1a) is structurally and functionally the best studied member of the P-type ion-translocating ATPases (1, 2). Located in the sarcoplasmic reticulum membrane, SERCA1 pumps Ca 2ϩ released into muscle cells during contraction and thereby causes relaxation. The reaction cycle consists of at least eight intermediates, and crystal structures have been determined for six of them (3-9). These crystal structures show that SERCA1 consists of three cytoplasmic domains (A, actuator; N, nucleotide binding; and P, phosphorylation) and 10 (M1-M10) transmembrane helices (3). They also demonstrate that ATPase undergoes large and global conformational changes during the reaction cycle. In conventional E1/E2 theory (10-12), active transport of Ca 2ϩ is achieved by alternating the affinity and accessibility of the transmembrane Ca 2ϩ -binding sites. That is, in E1, the binding sites have high affinity and face the cytoplasm; in E2, the binding sites have low affinity to Ca 2ϩ and face the lumen of the sarcoplasmic reticulum. Although H ϩ and water, instead of Ca 2ϩ , stabilize the binding sites in E2 (13), this form of the ATPase is unstable, particularly when solubilized (14). Therefore, so far all successful crystallization experiments in the absence of Ca 2ϩ used inhibitors that stabilize the transmembrane domain.Several inhibitors specific to SERCA1 are available (15-17). By far the best known and most potent inhibitor is thapsigargin (TG), a plant sesquiterpene lactone (18), with the dissociation constant in the subnanomolar range (15). Another commonly used inhibito...

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“…This hypothesis has been developed by the use of specific inhibitors of the ER Ca 2+-ATPase, such as cyclopiazonic acid (CPA, ref. 6) and thapsigargin, that could empty the Ca 21 in the ER without any known interaction with receptor-mediated cell signaling (3). More recently, the model has been shown to be applicable to intact endothelial cells and to have an important functional significance: the Ca 2+-ATPase inhibitors induced an endothelial NOmediated vasorelaxation that was exclusively dependent on the extracellular Ca 21 (2).…”

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Tyrosine Kinase May Participate in Ca2+ Entry for Endothelial Nitric Oxide Production

Hisayama

Kida

Imada

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-We have suggested that cyclopiazonic acid (CPA), a Ca 2+-ATPase inhibitor, produces nitric oxide (NO) by triggering a Ca2+-influx resulting from Ca 2+-depletion in the endoplasmic reticulum of endothelial cells. The tyrosine kinase inhibitor methyl 2,5-dihydroxycinnamate, while having no effect on relaxations induced by A23187 or Na nitroprusside, did inhibit the CPA-induced relaxation and cyclic GMP formation in rat aorta. Tyrosine kinase may participate in endothelial NO synthesis through activation of a Ca 2' entry mechanism.

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Cyclopiazonic acid inhibition of the Ca2+-transport ATPase in rat skeletal muscle sarcoplasmic reticulum vesicles

Cited by 185 publications

References 11 publications

Cyclopiazonic acid biosynthesis gene cluster gene cpaM is required for speradine A biosynthesis

Cyclopiazonic acid biosynthesis gene cluster gene cpaM is required for speradine A biosynthesis

Interdomain communication in calcium pump as revealed in the crystal structures with transmembrane inhibitors

Tyrosine Kinase May Participate in Ca2+ Entry for Endothelial Nitric Oxide Production

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