title: Hydroxylated xestospongins block inositol-1,4,5-trisphosphate-induced Ca2+ release and sensitize Ca2+-induced Ca2+ release mediated by ryanodine receptors.
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.
authors.affiliation: Center for Children's Environmental Health, University of California, Davis, 95616, USA.
authors.forename: Tram Anh
authors.initials: TA
authors.lastname: Ta
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Tadeusz F
authors.initials: TF
authors.lastname: Molinski
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: 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
chemical_list: 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