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Effects of marine toxins on smooth muscle contractile mechanism

海洋毒素对平滑肌收缩机制的影响

基本信息

批准号：
63480088
负责人：
KARAKI Hideaki
金额：
$ 4.42万
依托单位：
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-63480088/
关键词：
Smooth Muscle Contractile proteins Okadaic acid Calyculin A Phosphatase inhibitor 脱リン酸化酵素

项目摘要

Okadaic acid (OA)^2 and calyculin A (CLA) are toxins isolated from marine sponges. OA at lower concentrations inhibited the contractions in smooth muscle and at higher concentrations it induced a contraction. By contrast, CLA at lower concentrations transiently relaxed and then contracted smooth muscle. Both OA and CLA increased cytosolic Ca^<2+> levels which occurred after the development of muscle contraction. Contractions induced by these toxins were not inhibited in the absence of external Ca^<2+>, suggesting that contraction induced by these toxins is not attributable to the increase in cytosolic Ca^<2+> level. The contraction induced by OA and CLA followed the increase in myosin light chain phosphorylation which was not inhibited by Ca^<2+> -removal or calmodulin inhibitors. These toxins did not directly activate myosin light chain kinase or C kinase. Howver, OA at lower concentrations inhibited type 2A protein phosphatase and at higher concentrations it also inhibited type 1 phosphatase. By contrast, CLA at lower concentrations inhibited both type 2A and type 1 phosphatases. Phosphatase isolated from smooth muscle was inhibited by higher concentrations of OA and by lower concentrations of CLA, suggesting that phosphatase in smooth muscle is type 2A. However, smooth muscle phosphatase was not inhibited by "Inhibitor 2", indicating that it belongs to type 2A. OA and CLA may inhibit this phosphatase and increase relative activity of Ca^<2+> - and calmodulin-independent myosin light chain kinase to induce contraction. Since the inhibitory effect of lower concentrations of OA was similar to that of cyclic AMP, lower concentrations of OA may inhibit the phosphatase which antagomizes the effect of cyclic AMP-dependent protein kinase to induce smooth muscle relaxation.

冈田酸(OA)^2和花盏花素A(CLA)是从海绵中分离出来的毒素。较低浓度的油酸抑制血管的收缩，较高浓度的油酸引起收缩。相比之下，较低浓度的共轭亚油酸短暂地松弛然后收缩平滑肌。OA和CLA均增加了发生在肌肉收缩后的胞内Ca~(2+)水平。在无外源Ca~(2+)的情况下，这些毒素引起的收缩不受抑制，说明这些毒素引起的收缩不是细胞内Ca~(2+)&gt；水平升高所致。OA和CLA引起的收缩伴随着肌球蛋白轻链磷酸化的增加，而这种作用不被钙离子清除或钙调蛋白抑制剂所抑制。这些毒素不能直接激活肌球蛋白轻链或C激酶。然而，较低浓度的OA抑制2A型蛋白磷酸酶，而较高浓度的OA也抑制1型磷酸酶。相比之下，较低浓度的共轭亚油酸同时抑制了2A型和1型磷酸酶。从平滑肌中分离出的磷酸酶可被较高浓度的OA和较低浓度的CLA抑制，表明平滑肌中的磷酸酶为2A型。而“抑制物2”对平滑肌磷酸酶无抑制作用，提示其属于2A型。OA和CLA可抑制这种磷酸酶，增加钙和钙调素非依赖性肌球蛋白轻链激酶的相对活性，从而诱导收缩。由于较低浓度的OA的抑制作用与cAMP相似，因此较低浓度的OA可能抑制磷酸酶，从而拮抗cAMP依赖的蛋白激酶诱导的平滑肌松弛作用。

项目成果

期刊论文数量（40）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ishihara H,Ozaki H,Sato K,Hori M,Karaki H,Watabe S,Kato Y,Fusetani N,Hashimoto K,: "Calcium-independent aceivaeion Ω contraceile apparatus in smooth muscle by calyculin A" Uemura D and Hart shorne DJ.Jourual of Pharmacology and Experimeutal Therapputics.

Ishihara H、Ozaki H、Sato K、Hori M、Karaki H、Watabe S、Kato Y、Fusetani N、Hashimoto K：“Calyculin A 平滑肌中钙独立的 aceivaeion Ω 避孕装置” Uemura D 和 Hart shorne DJ。药理学和实验治疗学杂志。