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

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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