Establishment of the pharmacological sciences to elucidate the signal transduction system.

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One of the aims of this research project was to elucidate and control the mechanisms by which the intracellular second messenger systems transduce signals derived from extracellular stimuli, using specific molecular probes. The other was to create novel function-targeted probes which are useful to investigate the intracellular mechanisms. Such a pharmacological approach is undoubtedly powerful since various biological phenomena are controlled by a network of multiple intracellular messenger systems. Through three-year work under this grant, increasing number of specific molecular probes have became available, which enabled us to understand intracellular messenger systems. A good example is KN-62 and 93, specific inhibitors of Ca/calmodulin-dependent protein kinase II,which have been widely used to investigate the functions of the kinase. We also succeeded to purify the novel type of Ca/calmodulin-dependentkinase. V.We obtained evidence concerning signal transduction mechanisms by tachykinin, GABA and serotonin in neurons using pharmacological agents. Nitric oxide was demonstrated to be involved in the neural control of the brain vessel dilation.From an molecular biological approach, two types of Ca channels releasing Ca^<2+>from the intracellular store sites have been cloned. All these findings indicate that novel specific probes are desperately required for fundamental understanding of the intracellular messenger systems. Furthermore, these probes may provide a clue to create new compounds for a clinical use.