Pharmacological studies on toxins from marine organism

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Maitotoxin (MTX) is a water-soluble toxin isolated from the dinoflagellate Gambierdiscus toxicus. We reported for the first time that MTX activates voltage-independent Ca^<2+> channels on the cardiac plasma membrane. MTX caused aggregation of rabbit washed platelets. The cytosolic Ca^<2+> concentration ([Ca^<2+>] i) was also increased by the presence of MTX.The MTX-induced platelet aggregation and [Ca^<2+>] i-increase were totally abolished in a Ca^<2+>-free solution. These results suggest that the MTX-induced platelet activation is caused by an enhanced Ca^<2+>-influx presumably through voltage-independent Ca^<2+> channels.Zooxanthellatoxin-A (ZT-A) was isolated from a symbiotic marine alga, and the structure of ZT-A was determined to be a 62-membered lactone. ZT-A caused aggregation in rabbit platlets, but did not cause platelet aggregation or infcrease [Ca^<2+>] i in a Ca^<2+>-free solution. Indomethacin and SQ-29548 inhibited platelet aggregation and the increase in [Ca^<2+>] i ind … More uced by ZT-A.These results suggest that ZT-A elicited Ca^<2+>-influx from platelet plasma membranes. The resulting increase in [Ca^<2+>] i subsequently stimulates the secondary release of TXA_2 from platelets.In platlets ZT-A caused concentration-dependent protein tyrosine phosphorylation of 42kDa in the presence of 1mM Ca^<2+>. The protein tyrosine phosphorylation was inhibited by genistein. The 42kDa protein was identified as p42^<mapk> by immunoprecipitation with an anti-mitogen-activated protein kinase (MAPK) antibody. ZT-A released thromboxame (TX) B_2 and stimulated the liberation of arachidonic acid. ZT-A-induced TXB_2 release was completely inhibited by indomethacin, while the MARK activation was partially inhibited by it. These results suggest that ZT-A may activate a protein tyrosine kinase in the presence of external Ca^<2+>. The activated protein tyrosin kinase subsequently activates MAPK.The activation of MAPK in turn causes the liberation of arachidonic acid via phospholipase A_2, resulting in the release of TXA_2 from platelets. The detailed pharmacological studies suggest that the phospolipase A_2 activation is relevant to a protein tyrosine kinase. Less