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Development of the inhibitor for store-operated Ca^<2+> channel and its apply for treatment of diseases.

钙池操纵的Ca^2通道抑制剂的研制及其在疾病治疗中的应用。

基本信息

批准号：
12557155
负责人：
DOHI Toshihiro
金额：
$ 8.64万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Store-operated Ca^<2+> channel (SOC) and receptor-operated Ca^<2+> channel (ROC) play important roles for development of cellular functions in variety of cells including especially non-excitable cells such as immune- and inflammatory-related cells and salivary gland cells as well as excitable cells. SOC and ROC are the target for novel type of drugs. The present research studied the signal transaction for regulating Ca^<2+> entry through plasma memlane and searched the inhibitor of SOC and its possible apply for treatment of disease.1. Pituitary adenylate cyclase activating polypeptide (PACAP) activated large and long-lasting Ca^<2+> entry in bovine adrenal chromaffin cells. Some but not all inhibitors of SOC inhibited PACAP-induced entry. PACAP activated novel ROC independently from SOC and volltage-dependent Ca^<2+> channel.2. Interleukin-1 inhibited Ca^<2+> entry by stimulating the synthesis of un-identified protein.3. Increase in intracellular Ca^<2+> concentration ([Ca^<2+>]i) by … More ACh was blocked by 8Br-cADPR, an inhibitor of cyclic ADP-ribose, and by inhibition of calcinurin with FK506 and rapamycin. SOC inhibitor, SK&F 96365 inhibited ACh-induced rise and in the presence of SK&F 96365, the inhibitory effect of 8Br-cADPR disappeared.4. Methylxanthine, caffeine and theophyllin, inhibited the contraction of gunea-pig bronchial smooth muscle induced by histamine and LTD4, but not Ach and excess KCl. This effect of methylxanthine was remarkable in the presence of extracellular Ca^<2+>.5. The contraction induced by SOC activator, thapsigargin, was especially blocked by caffeine and theopylline. The contaction induced by Ca^<2+> ionophore was not inhibited6. The relaxing effect of theophylline was not inhibited by an inhibitor of adenosine receptor or A-kinase inhibitor.These results suggest the regulating mechanism for intracellular Ca^<2+> dynamics and suggest that methylxanthine has the inhibitory effect of SOC and relaxating effect of bronchial smooth muscle and provide a possibility of development of novel compound for SOC and the medicament for treatment of such disease as bronchial asthma. Less

钙库操纵的钙通道（SOC）和受体操纵的钙通道（ROC）在多种细胞中发挥重要作用，尤其是在非兴奋性细胞如免疫和炎症相关细胞和唾液腺细胞以及兴奋性细胞中。SOC和ROC是新型药物的靶点。本研究通过对细胞膜Ca^2+内流信号转导的研究，寻找SOC抑制剂及其在疾病治疗中的应用.在牛肾上腺嗜铬细胞中，腺苷酸环化酶激活多肽（PACAP）可激活大量且持久的Ca^2+内流。一些但不是所有的SOC抑制剂抑制PACAP诱导的进入。PACAP激活新的ROC独立于SOC和电压依赖性Ca^2+通道。白细胞介素-1通过刺激未鉴定蛋白的合成来抑制Ca^<2+>内流.细胞内Ca^<2+>浓度（[Ca^<2+]i）增加， ...更多信息 ACh被环ADP核糖抑制剂8Br-cADPR阻断，并被FK 506和雷帕霉素抑制钙调磷酸酶阻断。SOC抑制剂SK&F 96365抑制ACh诱导的升高，在SK&F 96365存在下，8Br-cADPR的抑制作用消失.甲基黄嘌呤、咖啡因和茶碱可抑制组胺和LTD_4引起的豚鼠支气管平滑肌收缩，但对Ach和过量KCl无明显抑制作用。在细胞外Ca^<2+>存在的情况下，甲基黄嘌呤的这种作用是显著的。由SOC激活剂毒胡萝卜素诱导的收缩尤其被咖啡因和茶碱阻断。Ca^<2+>离子载体诱导的接触没有被抑制6.茶碱的舒张作用不被腺苷受体抑制剂或A激酶抑制剂所抑制，提示其调节细胞内Ca^2+动力学的机制，并提示甲基黄嘌呤具有抑制SOC的作用和舒张支气管平滑肌的作用，为开发新的SOC化合物和治疗支气管哮喘等疾病的药物提供了可能。少