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

钙离子通道(SOC)和受体钙离子通道(ROC)在多种细胞的功能发育中起着重要作用，尤其是非兴奋性细胞，如免疫和炎症相关细胞、唾液腺细胞以及兴奋性细胞。SOC和ROC是新型药物的靶点。本研究研究了通过血浆膜调节Ca~(2+)~(2+)内流的信号转导，寻找SOC的抑制剂及其在疾病治疗中的可能应用。垂体腺苷环化酶激活多肽(PACAP)可激活牛肾上腺嗜铬细胞长时间大量钙离子内流。部分(但不是全部)SOC抑制剂可抑制PACAP诱导的内流。结论：1.PACAP独立于SOC和电压依赖性钙通道激活新的ROC。白介素1通过刺激未知蛋白的合成，抑制钙离子内流。…对细胞内[Ca~(2+)]_2浓度的影响环状ADP核糖抑制剂8BR-cADPR以及FK506和雷帕霉素抑制钙调神经磷酸酶可阻断更多的ACh。SOC抑制剂SK&F 96365可抑制ACh的升高，在SK&F 96365的存在下，8BR-cADPR的抑制作用消失。甲基黄嘌呤、咖啡因和茶碱能抑制组胺和LTD4引起的豚鼠支气管平滑肌收缩，但不能抑制乙酰胆碱和过量KCl引起的收缩。在胞外Ca~(2+)和Gt；存在的情况下，甲基黄嘌呤的这种作用显著。SOC激动剂thapsigargin引起的收缩特别被咖啡因和茶碱阻断。钙离子载体引起的接触不受抑制。茶碱的松弛作用不被腺苷受体抑制剂或A-激酶抑制剂所抑制。这些结果提示了细胞内钙动力学的调节机制，提示甲基黄嘌呤具有SOC的抑制作用和支气管平滑肌的松弛作用，为开发新型的SOC化合物和治疗哮喘等疾病的药物提供了可能性。较少

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