ELUCIDATION OF THE INTRACELLULAR CALCIUM SIGNAL TRANSDUCTION WITH THE MOLECULAR PHARMACOLOGICAL APPROARCH

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Research on cellular signals, which depend heavily on physiological, biochemical and enzymatic studies, has made a rapid progress in the last 10 years with the break through introduction of such molecular biotogical approach as cDNA cloning. We studied molecular basis of the intracellular calcium signal transduction system by protein chemical, molecular biological, and molecular pharmacological approach. We have examined the mechanisms by which a novel Ca2+/calmodulin-dependent protein kinase V(CaM kinase V) was activated by phosphorylation. Physicochemical or biochemical properties of CaM kinase V were also analyzed Furthermore, polyclonal antibody against CaM kinase V was prepared and tissue distribution and immunohistochemical localization of CaM kinase V were studied. We have then discovered the CaM kinase V-activator which was necessary for CaM kinase V catalytic activity. Interestingly, the CaM kinase V-activator did phosphorylate Ca2+/calmodulin-dependent protein kinase IV(CaM kinase IV)associated with its activation. Finally, we suggested that there were new CaM kinase cascades such as those of MAP kinase. We have been studying to analyze biological function using synthesized molecule to activate or inhibit the activities of the target molecule. Based on these studies in creating designed molecular probes acting in the intracellular signal transduction, we have clarified the physiological functions of the CaM kinase which are closely linked to the intracellular signal transduction. Recently, we have cloned two new Ca2+/calmodulin-dependent protein kinase I(CaM kinase I) isoforms from rat brain and CaM kinase V has been thought to be an isoform of CaM kinase I.