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

阐明海洋天然产物对血小板和肌肉细胞的兴奋作用机制

• 批准号: 08457603
• 负责人: OHIZUMI Yasushi
• 金额: $ 4.8万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457603/
• 关键词: marine products; plateles; muscle cells; Ca^<2+>; platelete aggregation; ATPase; thromboxane A_2; 9-methyl-7-bromoeudistomin D; Ca^<2+>遊離チャネル; BKチャネル; 形態変化; 蛋白リン酸化; IIb-IIIa; 筋収縮

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.

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。

项目成果

Rho, M-C.et al.: "The mode of rabbit pkatelet shape change and aggregation induced by theonezolide A,a novel polyketide macrolide,isolated from the Okinawan marine sponge Theonella sp." Can.J.Physiol.Pharmacol.74. 193-199 (1996)

Rho, M-C. 等人：“Theonezolide A（一种新型聚酮化合物大环内酯，从冲绳海绵 Theonella sp 中分离出来）诱导兔 pkatelet 形状变化和聚集的模式。”

M. Ohkura: "Characteristics of ^<45>Ca^<2+> release induced by quinolidomicin Al, a 60-membered macrolide from skeletal muscle sarcoplasmic reticulum." BIOCHIMICA ET BIOPHYSICA ACTA. 1294. 177-182 (1996)

M. Ohkura：“喹诺多霉素Al（一种来自骨骼肌肌浆网的60元大环内酯）诱导的^<45>Ca^<2>释放的特征。”

Ohizumi, Y.et al.: "Ptilomycalin A,a novel Na+,K+ orCa2+-ATPase inhibitor,competitively interacts with ATP at its binding site" European Journal of Pharmacology. 310. 95-98 (1996)

Ohizumi, Y. 等人：“Ptilomycalin A，一种新型 Na、K 或 Ca2 -ATP 酶抑制剂，在其结合位点与 ATP 竞争性相互作用”《欧洲药理学杂志》。

Y. Imaizumi: "Characteristics of Ca^<2+> release for activation of K^+ current and contractile system in some smooth muscles." AMERICAN JOURNAL OF PHYSIOLOGY. 271. C772-C782 (1996)

Y. Imaizumi：“Ca ^ 2 释放用于激活某些平滑肌中 K ^ 电流和收缩系统的特征。”

Ohizumi, Y.et al.: "Ptilomycalin A,a novel Na^+, K+or Ca2+-ATPase inhibitor, competitively interacts wiht ATP at its binding site" European Journal of Pharmacology. 310. 95-98 (1996)

Ohizumi, Y.等人：“Ptilomycalin A，一种新型 Na+、K 或 Ca2+-ATP 酶抑制剂，在其结合位点与 ATP 竞争性相互作用”《欧洲药理学杂志》。