Elucidation of the mechanism of excitatory action of marine natural products on platelets and muscle cells

我们在筛选海洋生物天然产物的过程中，不仅对基础研究有用，而且对多种疾病的治疗也有用，我们研究了这些化合物的作用机制。从培养的海藻中分离到一种新的单胞单酰基甘油三酯，对血小板聚集有抑制作用。一种新型聚酮类大环内酯类药物噻奥奈唑内酯- a （tza）引起血小板形状的明显改变。我们对该化合物的药理研究表明，TZ-A是阐明信号转导机制的有用化学工具。来自共生鞭毛藻的Zooxanthellatoxin-A （ZT-A）引起Ca^<2+>-或血栓素a_2依赖性和基因敏感的血小板聚集。这表明ZT-A首先激活蛋白酪氨酸激酶，激活的蛋白酪氨酸激酶随后可能通过PLC-gamma2和PKC刺激丝裂原激活的蛋白激酶的激活。另一方面，ptilomycalin A已被证明在Na^+， K^+-ATP酶或Ca^<2+>-ATP酶的ATP结合位点与ATP竞争性相互作用，导致这两种酶的抑制。最近，我们发现了9-甲基-7-溴-白屈胃素D，这是最强大的咖啡因类物质，但咖啡因不能诱导皮肤平滑肌收缩。这些数据表明细胞内Ca^<2+>储存由两种功能不同的类型组成。这些研究得出的结论是，这些天然产物不仅可以作为药理工具，而且可以作为新药开发的先导化合物。

In our screening program for natural products from marine organisms, useful not only for basic researches but also for the treatment of a variety of diseases, we have studies the mechanism of action of these compounds. The new monogalactopyranosylacylglyceroI was isolated from the cultured marine alga and caused an inhibition of platelet aggregation. Theonezolide-A (TZ-A), a novel polyketide macrolide caused a marked platelet shape change. Our pharmacological studies on this compound suggest that TZ-A is a useful chemical tool for clarifying the signal transduction mechanism. Zooxanthellatoxin-A (ZT-A) from a symbiotic dinoflagellate caused Ca^<2+>-or thromboxane A_2-dependent and genestin-sensitive aggregation of platelets. It is suggested that ZT-A primarily activate a protein tyrosine kinase and that the activated protein tyrosine kinase subsequently stimulates the activation of mitogen-activated protein kinase probably via PLC-gamma2 and PKC.On the other hand, ptilomycalin A has been showm to interacts competitively with ATP at the ATP binding site of Na^+, K^+-ATPase or Ca^<2+>-ATPaase, resulting in inhibition of both the enzymes. Recently, we have found that 9-methyl-7-bromo-eudistomin D,the most powerful caffeine like substances not but caffeine failed to induce a contraction of skinned smooth muscles. These data suggest that intracellular Ca^<2+> stores consist of two functional distinct types. These studies lead to the conclusion that these natural products are useful not only as pharmacological tools but also as leading compounds for new drug development.