4, 6‐Dibromo‐3‐hydroxycarbazole (an analogue of caffeine‐like Ca2+ releaser), a novel type of inhibitor of Ca2+‐induced Ca2+ release in skeletal muscle sarcoplasmic reticulum

Yukiko Takahashi, Ken‐Ichi ‐I Furukawa, Daiske Kozutsumi, Masami Ishibashi, Jun'ichi Kobayashi, Yasushi Ohizumi

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9 Citations (Scopus)


4,6‐Dibromo‐3‐hydroxycarbazole (DBHC) was synthesized as an analogue of bromoeudistomin D (BED), a powerful Ca2+ releaser, and its pharmacological properties were examined. In Ca2+ electrode experiments, DBHC (100 μm) markedly inhibited Ca2+ release from the heavy fraction of sarcoplasmic reticulum (HSR) induced by caffeine (1 mm) and BED (10 μm). DBHC (0.1 to 100 μm) inhibited 45Ca2+ release induced by Ca2+ from HSR in a concentration‐dependent manner. DBHC (100 μm) abolished 45Ca2+ release induced by caffeine (1 mm) and BED (10 μm) in HSR. Inhibitory effects of calcium‐induced calcium release (CICR) blockers such as procaine, ruthenium red and Mg2+ on 45Ca2+ release were clearly observed at Ca2+ concentrations from pCa 7 to pCa 5.5, and were decreased at Ca2+ concentrations higher than pCa 5.5 or lower than pCa 7. However, DBHC decreased Ca2+ release induced by Ca2+ over the wide range of extravesicular Ca2+ concentrations. [3H]‐ryanodine binding to HSR was suppressed by ruthenium red, Mg2+ and procaine, but was not affected by DBHC up to 100 μm. [3H]‐ryanodine binding to HSR was enhanced by caffeine and BED. DBHC antagonized the enhancement in a concentration‐dependent manner. 9‐[3H]‐Methyl‐7‐bromo‐eudistomin D, an 3H‐labelled analogue of BED, specifically bound to HSR. Both DBHC and caffeine increased the KD value without affecting the Bmax value, indicating a competitive mode of inhibition. These results suggest that DBHC binds to the caffeine binding site to block Ca2+ release from HSR. This drug is a novel type of inhibitor for the CICR channels in SR and may provide a useful tool for clarifying the Ca2+ releasing mechanisms in SR. 1995 British Pharmacological Society

Original languageEnglish
Pages (from-to)941-948
Number of pages8
JournalBritish Journal of Pharmacology
Issue number5
Publication statusPublished - 1995 Mar


  • 4,6‐Dibromo‐3‐hydroxycarbazole
  • Ca‐induced Ca release
  • Mg
  • bromoeudistomin D
  • caffeine
  • procaine
  • ruthenium red
  • ryanodine binding
  • sarcoplasmic reticulum
  • skeletal muscle

ASJC Scopus subject areas

  • Pharmacology

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