Tyrosine kinase inhibitors suppress prostaglandin F2alpha-induced phosphoinositide hydrolysis, Ca2+ elevation and contraction in iris sphincter smooth muscle.
Tyrosine kinase inhibitors suppress prostaglandin F2alpha-induced phosphoinositide hydrolysis, Ca2+ elevation and contraction in iris sphincter smooth muscle.
复制标题
酪氨酸激酶抑制剂可抑制前列腺素 F2α 诱导的磷酸肌醇水解、Ca2 升高和虹膜括约肌平滑肌收缩。
DOI：
10.1016/s0014-2999(98)00697-9
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发表时间：
1998
影响因子：
5
通讯作者：
Abdel-Latif,AA
中科院分区：
文献类型：
--
作者：
Yousufzai,SY;Abdel-Latif,AA
我们研究了蛋白酪氨酸激酶抑制剂金雀异黄酮、酪氨酸磷酸酶 47 和除草霉素对前列腺素 F2α 和卡巴胆碱诱导的肌醇 1,4,5-三磷酸 (IP3) 产生、猫虹膜括约肌平滑肌 [Ca2+] 固定和收缩的影响。前列腺素F2α和卡巴胆碱以浓度依赖性方式诱导收缩，EC50值分别为0.92×10−9和1.75×10−8M。蛋白酪氨酸激酶抑制剂阻断前列腺素 F2α 对 IP3 积累、[Ca2+] 固定和收缩的刺激作用，但不能阻断由卡巴胆碱引起的刺激作用，表明蛋白酪氨酸激酶活性参与前列腺素的生理作用。黄豆苷元和酪氨酸磷酸酶 A，分别是金雀异黄酮和酪氨酸磷酸酶 47 的无活性阴性对照化合物，没有效果。拉坦前列素是一种前列腺素 F2α 类似物，用作抗青光眼药物，可诱导收缩，但这种作用被金雀异黄素阻断。金雀异黄素 (10 μM) 显着降低（67%）前列腺素 F2α 刺激的 [Ca2+]i 增加，但对猫虹膜括约肌平滑肌细胞中卡巴胆碱的影响很小。钒酸盐是蛋白酪氨酸磷酸酶的有效抑制剂，以浓度依赖性方式诱导缓慢的肌肉收缩，EC50 为 82 μM，并以浓度依赖性方式增加 IP3 生成，EC50 为 90 μM。金雀异黄素 (10 μM) 消除了钒酸盐的影响。 Wortmannin 是一种肌球蛋白轻链激酶抑制剂，可减少前列腺素 F2α 和卡巴胆碱诱导的收缩，表明蛋白酪氨酸激酶活性的参与可能位于前列腺素 F2α 引起的 [Ca2+] 增加的上游。进一步研究旨在阐明蛋白酪氨酸激酶活性在前列腺素F2α受体激活和细胞内Ca2+动员增加之间的耦合机制中的作用，并鉴定酪氨酸磷酸化底物，将为蛋白酪氨酸激酶在平滑肌收缩机制中的作用以及前列腺素降低青光眼患者眼压作用的机制提供重要信息。
We investigated the effects of the protein tyrosine kinase inhibitors, genistein, tyrphostin 47, and herbimycin on prostaglandin F2α- and carbachol-induced inositol-1,4,5-trisphosphate (IP3) production, [Ca2+]imobilization and contraction in cat iris sphincter smooth muscle. Prostaglandin F2αand carbachol induced contraction in a concentration-dependent manner with EC50values of 0.92×10−9and 1.75×10−8M, respectively. The protein tyrosine kinase inhibitors blocked the stimulatory effects of prostaglandin F2α, but not those evoked by carbachol, on IP3accumulation, [Ca2+]imobilization and contraction, suggesting involvement of protein tyrosine kinase activity in the physiological actions of the prostaglandin. Daidzein and tyrphostin A, inactive negative control compounds for genistein and tyrphostin 47, respectively, were without effect. Latanoprost, a prostaglandin F2αanalog used as an antiglaucoma drug, induced contraction and this effect was blocked by genistein. Genistein (10 μM) markedly reduced (by 67%) prostaglandin F2α-stimulated increase in [Ca2+]ibut had little effect on that of carbachol in cat iris sphincter smooth muscle cells. Vanadate, a potent inhibitor of protein tyrosine phosphatase, induced a slow gradual muscle contraction in a concentration-dependent manner with an EC50of 82 μM and increased IP3generation in a concentration-dependent manner with an EC50of 90 μM. The effects of vanadate were abolished by genistein (10 μM). Wortmannin, a myosin light chain kinase inhibitor, reduced prostaglandin F2α- and carbachol-induced contraction, suggesting that the involvement of protein tyrosine kinase activity may lie upstream of the increases in [Ca2+]ievoked by prostaglandin F2α. Further studies aimed at elucidating the role of protein tyrosine kinase activity in the coupling mechanism between prostaglandin F2αreceptor activation and increases in intracellular Ca2+mobilization and identifying the tyrosine-phosphorylated substrates will provide important information about the role of protein tyrosine kinase in the mechanism of smooth muscle contraction, as well as about the mechanism of the intraocular pressure lowering effect of the prostaglandin in glaucoma patients.