TY - JOUR
T1 - Hydroxylated xestospongins block inositol-1,4,5-trisphosphate-induced Ca2+ release and sensitize Ca2+-induced Ca2+ release mediated by ryanodine receptors
AU - Tram, Anh Ta
AU - Feng, Wei
AU - Molinski, Tadeusz F.
AU - Pessah, Isaac N
PY - 2006
Y1 - 2006
N2 - 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 Ca 2+ signals in most animal cells. Xestospongin C (XeC) was shown to selectively block IP3-induced Ca2+ release and IP 3R-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-OHXeA, 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 Ca 2+-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.
AB - 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 Ca 2+ signals in most animal cells. Xestospongin C (XeC) was shown to selectively block IP3-induced Ca2+ release and IP 3R-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-OHXeA, 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 Ca 2+-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.
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U2 - 10.1124/mol.105.019125
DO - 10.1124/mol.105.019125
M3 - Article
C2 - 16249374
AN - SCOPUS:31044446068
VL - 69
SP - 532
EP - 538
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -