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

在我们的海洋生物天然产物筛选计划中，我们研究了这些化合物的作用机理。海洋生物天然产物不仅对基础研究有用，而且对各种疾病的治疗也很有用。新的单半乳糖吡喃糖酰甘油I是从培养的海洋藻类中分离出来的，并能抑制血小板聚集。茶酮-A(TZ-A)是一种新型的聚酮大环内酯类化合物，可引起明显的血小板形态改变。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。甲藻共生的甲藻毒素A(ZT-A)可引起血栓素A2或血栓素A2依赖性和基因敏感的血小板聚集。提示ZT-A首先激活一个蛋白酪氨酸激酶，然后激活的蛋白酪氨酸激酶可能通过PLC-Gamma2和PKC来刺激丝裂原激活的蛋白激酶的激活。另一方面，已经证明Ptilmycalin A与ATP在Na~+，K~+-ATPase或Ca^&lt；2+&gt；-ATPaase的结合部位竞争性地相互作用，导致这两种酶的抑制。最近，我们发现9-甲基-7-溴代丁二烯D，最强的咖啡因类物质，而不是咖啡因，未能诱导皮肤平滑肌肉的收缩。这些数据表明，细胞内的钙离子储存由两种不同的功能类型组成。这些研究得出的结论是，这些天然产物不仅用作药理工具，而且还用作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.