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Hydroxylated Xestospongins Block Inositol-1,4,5-trisphosphate-Induced Ca²⁺ Release and Sensitize Ca²⁺-Induced Ca²⁺ Release Mediated by Ryanodine Receptors

Center for Children's Environmental Health (T.A.T., I.N.P.), Department of Veterinary-Molecular Biosciences (T.A.T., W.F., I.N.P.), and Department of Chemistry (T.F.M.), University of California, Davis, California

Inositol-1,4,5-trisphosphate receptors (IP₃Rs) and ryanodine receptors (RyRs) often coexist within the endoplasmic/sarcoplasmic reticulum (ER/SR) membrane and coordinate precise spatial and temporal coding of Ca²⁺ signals in most animal cells. Xestospongin C (XeC) was shown to selectively block IP₃-induced Ca²⁺ release and IP₃R-mediated signaling (Gafni et al., 1997). We have further studied the specificity of xestospongin structures possessing ring hydroxyl (-OH) substituents toward IP₃R, RyR, and ER/SR Ca²⁺-ATPase (SERCA) activities. XeC potently inhibits IP₃R, weakly inhibits RyR1, and lacks activity toward SERCA1 and SERCA2. XeD (9-OH XeC), 7-OH-XeA, and araguspongin C isolated from the marine sponge Xestospongia species also inhibit IP₃-mediated Ca²⁺ release and lack activity toward SERCA. However, these hydroxylated derivatives possess a unique activity in that they enhance Ca²⁺-induced Ca²⁺ release from SR vesicles by a mechanism involving the sensitization of RyR1 channels within the same concentration range needed to block IP₃-induced Ca²⁺ release. These results show that xestospongins and related structures lack direct SERCA inhibitory activity, as suggested by some previous studies. A new finding is that XeD and related structures possessing a hydroxylated oxaquinolizidine ring are IP₃R blockers that also enhance Ca²⁺-induced Ca²⁺ release mediated by RyRs. In intact cells, the actions of XeD are blocked by ryanodine pretreatment and do not interfere with thapsigargin-mediated Ca²⁺ mobilization stemming from SERCA block. Hydroxylated bis-oxaquinolizadine derivatives isolated from Xestospongia species are novel bifunctional reagents that may be useful in ascertaining how IP₃Rs and RyRs contribute to cell signaling.

Address correspondence to: Dr. Isaac Pessah, Department of VM: Molecular Biosciences University of California, Davis, 1 Shields Avenue, Davis, CA 95616. E-mail: inpessah{at}ucdavis.edu

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