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Title: Hydroxylated xestospongins block inositol-1,4,5-trisphosphate-induced Ca2+ release and sensitize Ca2+-induced Ca2+ release mediated by ryanodine receptors.

Authors: Ta, Tram Anh; Feng, Wei; Molinski, Tadeusz F; Pessah, Isaac N

Published In Mol Pharmacol, (2006 Feb)

Abstract: Inositol-1,4,5-trisphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs) often coexist within the endoplasmic/sarcoplasmic reticulum (ER/SR) membrane and coordinate precise spatial and temporal coding of Ca(2+) signals in most animal cells. Xestospongin C (XeC) was shown to selectively block IP(3)-induced Ca(2+) release and IP(3)R-mediated signaling (Gafni et al., 1997). We have further studied the specificity of xestospongin structures possessing ring hydroxyl (-OH) substituents toward IP(3)R, RyR, and ER/SR Ca(2+)-ATPase (SERCA) activities. XeC potently inhibits IP(3)R, 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 IP(3)-mediated Ca(2+) release and lack activity toward SERCA. However, these hydroxylated derivatives possess a unique activity in that they enhance Ca(2+)-induced Ca(2+) release from SR vesicles by a mechanism involving the sensitization of RyR1 channels within the same concentration range needed to block IP(3)-induced Ca(2+) 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 IP(3)R blockers that also enhance Ca(2+)-induced Ca(2+) release mediated by RyRs. In intact cells, the actions of XeD are blocked by ryanodine pretreatment and do not interfere with thapsigargin-mediated Ca(2+) mobilization stemming from SERCA block. Hydroxylated bis-oxaquinolizadine derivatives isolated from Xestospongia species are novel bifunctional reagents that may be useful in ascertaining how IP(3)Rs and RyRs contribute to cell signaling.

PubMed ID: 16249374 Exiting the NIEHS site

MeSH Terms: Alkaloids/chemistry; Alkaloids/pharmacology; Animals; Calcium Signaling/drug effects*; Calcium-Transporting ATPases/antagonists & inhibitors; Calcium/metabolism; Calcium/pharmacology; Hydroxylation; Inositol 1,4,5-Trisphosphate/antagonists & inhibitors*; Inositol 1,4,5-Trisphosphate/pharmacology; Macrocyclic Compounds; Mice; Muscle Fibers, Skeletal/drug effects; Muscle Fibers, Skeletal/metabolism; Oxazoles/chemistry; Oxazoles/pharmacology*; Quinolizines/chemistry; Quinolizines/pharmacology; Rats; Ryanodine Receptor Calcium Release Channel/drug effects*; Ryanodine/metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Xestospongia/chemistry

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