Biol. Pharm. Bull. 30(12) 2231—2237 (2007)

Cardiac electrical activity is generated by the summation of currents through multiple ion channels. The rate and force of contraction of the heart are precisely controlled by compartmentalized regulation of cardiac ion channels which determine the electrical activity. The ventricular action potential is characterized by a long-lasting so-called “plateau” period in which a balance is maintained fairly between small inward and outward currents. Small changes in this balance can have severe functional consequences, mostly in the cardiac repolarization process. Molecular identification of ion channels during the past twenty years has taught us not only complex of electrical formation but also specific targets for pharmacological intervention. In the last decade, the study of the genetic bases of inherited arrhythmogenetic diseases has achieved several milestones. Several genetic substrates of arrhythmias have been identified, and the functional characterization of mutant proteins has opened new perspectives about the possibility of performing gene-specific therapy. The genetic substrate of arrhythmia is surely a major risk factor (genetic factor), but there are other risk factors triggered mainly by regulation of cardiac ion channels (regulatory factors) (Fig. 1). It is known that modulation of cardiac ion channels, which is caused by drug administration, sympathetic nervous system stimulation and gender difference can increase risks of lethal arrhythmias in carriers of inherited disease mutations. These modulations are thought to also be involved in common cardiac arrhythmias. Because many signaling molecules are localized within single cells, an understanding of the molecular basis of compartmentalized regulation of cardiac channels is a key for understanding and treating the lethal arrhythmias. In terms of the compartmentalized regulation of cardiac ion channels, this review concerns drug access through the cell membrane, and receptor-mediated signaling by neurotransmitters and hormones based on my previous and recent data. In this review, I will introduce our research on molecular mechanisms of compartmentalized regulation of cardiac ion channels via drugs, cAMP and sex hormones that are summarized as a schematic diagram of cardiac ventricular myocytes (Fig. 2). LOCALIZED ACCESS TO THE 1,5-BENZOTHIAZEPINE SITE OF THE L-TYPE CA CHANNEL