Pacemaker current and automatic rhythms: toward a molecular understanding

The ionic basis of automaticity in the sinoatrial node and His-Purkinje system, the primary and secondary cardiac pacemaking regions, is discussed. Consideration is given to potential targets for pharmacologic or genetic therapies of rhythm disorders. An ideal target would be an ion channel that functions only during diastole, so that action potential repolarization is not affected, and one that exhibits regional differences in expression and/or function so that the primary and secondary pacemakers can be selectively targeted. The so-called pacemaker current, If, generated by the HCN gene family, best fits these criteria. The biophysical and molecular characteristics of this current are reviewed, and progress to date in developing selective pharmacologic agents targeting If and in using gene and cell-based therapies to modulate the current are reviewed.