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Stellettamide‐A, a novel inhibitor of calmodulin, isolated from a marine sponge
Author(s) -
Abe Yoshinori,
Saito Shinya,
Hori Masatoshi,
Ozaki Hiroshi,
Fusetani Nobuhiro,
Karaki Hideaki
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701282
Subject(s) - calmodulin , taenia coli , myosin light chain kinase , phosphodiesterase , contraction (grammar) , biochemistry , calcium , atpase , cyclic nucleotide phosphodiesterase , biology , chemistry , microbiology and biotechnology , myosin , enzyme , endocrinology , organic chemistry
Stellettamide A (ST‐A), a novel marine toxin isolated from a marine sponge, inhibited high K + (72.7 m M )‐induced contraction in the smooth muscle of guinea‐pig taenia coli with an IC 50 of 88 μ M . In the taenia permeabilized with Triton X‐100, ST‐A inhibited Ca 2+ (3 and 10 μ M )‐induced contractions with an IC 50 of 46 μ M for 3 μ M Ca 2+ and 105 μ M for 10 μ M Ca 2+ . In the permeabilized taenia, calyculin‐A (300 n M ), a potent inhibitor of type‐1 and type‐2A phosphatases, induced sustained contraction in the absence of Ca 2+ . ST‐A had no effect on this contraction. ST‐A inhibited Mg 2+ ‐ATPase activity in native actomyosin prepared from chicken gizzard with an IC 50 of 25 μ M . In a reconstituted smooth muscle contractile system containing calmodulin, myosin light chain (MLC) and MLC kinase, ST‐A inhibited MLC phosphorylation with an IC 50 of 152 μ M . The inhibitory effect of ST‐A was antagonized by increasing the concentration of calmodulin. ST‐A inhibited calmodulin activity, assessed by Ca 2+ /calmodulin‐dependent enzymes, (Ca 2+ ‐Mg 2+ )‐ATPase of erythrocyte membrane, with an IC 50 of 100 μ M and phosphodiesterase prepared from bovine cardiac muscle with an IC 50 of 52 μ M . The inhibitory effect on phosphodiesterase activity was antagonized by increasing the calmodulin concentration. Interaction between ST‐A and calmodulin was demonstrated by instantaneous quenching of the intrinsic tyrosine fluorescence of calmodulin by ST‐A (3–300 μ M ). Similar results were obtained in the presence or absence of Ca 2+ suggesting that ST‐A binds to calmodulin and that Ca 2+ is not essential for the binding of ST‐A to calmodulin. These results suggest that ST‐A, isolated from marine metabolites, is a novel inhibitor of calmodulin.