[Molecular pharmacology of intracellular Ca2+ messenger system in cardiovascular function: development and...

The importance of Ca2+ for the transmission of information inside living cells is well-recognized. The mobilized Ca2+ binds to the intracellular Ca2+ binding proteins to transmit the Ca2+ signal. Calmodulin is the most important Ca2+ binding protein to exert pleiotropic effects on various cellular functions by activating multiple enzymes. To determine the physiological significance of the Ca2+ messenger system, specific inhibitors are quite essential. We have been originally developing novel and selective inhibitors, and analyzing the several processes involved in information flow in the Ca(2+)-dependent regulatory system of cell functions. The aim of this review is to introduce our research strategy for the production of selective inhibitors towards calmodulin-dependent enzymes and to discuss recent progress in the understanding of the multiple calmodulin-dependent pathways that mediate the action of exogenous physiological stimuli. We summarize much of the pharmacological evidence that has led to our current knowledge of calmodulin-regulated cell functions, with emphasis on aspects that may be relevant to drug design. These H-series inhibitors are one of the most powerful tools as molecular probes for pharmacological approaches, and will shed light on the physiological significance and molecular mechanisms of the calmodulin-dependent pathways in various cell functions.