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Research ArticleCELLULAR AND MOLECULAR

Distinct Pharmacology of 2-Hydroxycarbazole-Induced Ca2+ Release in the Sea Urchin Egg

Justyn M. Thomas, Grant C. Churchill, Sandip Patel and Antony Galione
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 644-650;
Justyn M. Thomas
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Grant C. Churchill
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Sandip Patel
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Antony Galione
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Abstract

2-Hydroxycarbazole, a compound structurally related to the Ca2+-mobilizing marine toxin 9-methyl-7-bromoeudistomin, has recently been proposed to activate both type 1 and type 2 ryanodine receptors in skeletal and cardiac muscle, respectively. This study was undertaken to evaluate the activity of this compound in the sea urchin egg homogenate, a model system used to characterize intracellular Ca2+ mobilization mechanisms. 2-Hydroxycarbazole was found to potently release Ca2+ in a concentration-dependent manner via a specific mechanism displaying apparent desensitization. Use of selective inhibitors of the Ca2+-mobilizing messengers inositol 1,4,5-trisphosphate, cyclic adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate, as well as desensitization of homogenates to each of these molecules, failed to inhibit the response to 2-hydroxycarbazole. However, the response to 2-hydroxycarbazole was competitively antagonized by caffeine. Investigation of the Ca2+ stores accessed by 2-hydroxycarbazole revealed Ca2+ release from a thapsigargin-insensitive pool. Finally, 2-hydroxycarbazole failed to enhance [3H]ryanodine binding, suggesting the operation of a nonryanodine receptor mechanism. These results demonstrate that 2-hydroxycarbazole is acting to modulate a Ca2+ release mechanism with distinct pharmacological properties to those previously reported in the sea urchin egg.

Footnotes

  • This work was supported by the Wellcome Trust.

  • Abbreviations:
    IP3
    inositol 1,4,5-trisphosphate
    cADPR
    cyclic adenosine diphosphate ribose
    NAADP
    nicotinic acid adenine dinucleotide phosphate
    RyR
    ryanodine receptor
    CICR
    Ca2+-induced Ca2+ release
    DMSO
    dimethyl sulfoxide
    ANOVA
    analysis of variance
    • Received December 12, 2000.
    • Accepted March 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleCELLULAR AND MOLECULAR

Distinct Pharmacology of 2-Hydroxycarbazole-Induced Ca2+ Release in the Sea Urchin Egg

Justyn M. Thomas, Grant C. Churchill, Sandip Patel and Antony Galione
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 644-650;

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Research ArticleCELLULAR AND MOLECULAR

Distinct Pharmacology of 2-Hydroxycarbazole-Induced Ca2+ Release in the Sea Urchin Egg

Justyn M. Thomas, Grant C. Churchill, Sandip Patel and Antony Galione
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 644-650;
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