Xestospongin C is a potent inhibitor of SERCA at a vertebrate synapse.
The specificity of action of Xestospongin C (XeC) towards the inositol 1,4,5-trisphosphate (IP3) receptor has been studied using the frog neuromuscular junction. In perisynaptic Schwann cells (PSCs), glial cells at this synapse, Ca2+ stores are dependent upon IP3 activation. Bath application of XeC (700 nM) caused a transient calcium elevation and blocked Ca2+ responses evoked in PSCs by synaptic activity or various agonists (ATP, muscarine, adenosine) only when Ca2+ stores had previously been challenged with local application of agonists. Moreover, XeC occluded the effects of thapsigargin (tg; 2 microM), a blocker of the Ca2+ ATPase pump of internal stores, which failed to evoke Ca2+ transients following 20 min of exposure to XeC. In nerve terminals, where the Ca2+ stores are ryanodine-sensitive, application of XeC (700 nM) prolonged the recovery phase of Ca2+ transients evoked by single action potentials, due to a prolonged Ca2+ clearance in the nerve terminal. No effects of tg (2 microM) were observed on Ca2+ response evoked by nerve stimulation when applied on the preparation after XeC (700 nM). Conversely, XeC (700 nM) had no effect on the shape and duration of Ca2+ entry in nerve terminals when tg was applied before XeC. These results indicate that XeC acts as an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump of internal stores.
Centre de Recherche en Sciences Neurologiques, Université de Montréal, Que., H3C 3J7, Montréal, Canada. annie.castonguay@umontreal.ca
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Castonguay
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Robitaille
D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000201:enzymology; D010080:Oxazoles / Q000494:pharmacology*; D011894:Rana pipiens; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D012583:Schwann Cells / Q000187:drug effects / Q000201:enzymology; D013569:Synapses / Q000187:drug effects* / Q000201:enzymology; D019284:Thapsigargin / Q000494:pharmacology
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D018721:Muscarinic Agonists; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; C108644:xestospongin A; D019284:Thapsigargin; D009116:Muscarine; D000255:Adenosine Triphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D000241:Adenosine; D002118:Calcium