Hydroxylated xestospongins block inositol-1,4,5-trisphosphate-induced Ca2+ release and sensitize Ca2+-induced Ca2+ release mediated by ryanodine receptors.
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.
Ta
Tram Anh
TA
Center for Children's Environmental Health, University of California, Davis, 95616, USA.
Feng
Wei
W
Molinski
Tadeusz F
TF
Pessah
Isaac N
IN
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D006900:Hydroxylation; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047028:Macrocyclic Compounds; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011807:Quinolizines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D047131:Xestospongia / Q000737:chemistry
D000470:Alkaloids; C506944:Atp2a1 protein, mouse; C506945:Atp2a1 protein, rat; C506948:Atp2a2 protein, rat; D047028:Macrocyclic Compounds; D010080:Oxazoles; D011807:Quinolizines; D019837:Ryanodine Receptor Calcium Release Channel; C455173:araguspongine C; C108644:xestospongin A; C108642:xestospongin D; D012433:Ryanodine; D015544:Inositol 1,4,5-Trisphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases; D002118:Calcium