Mouse models for studying pacemaker channel function and sinus node arrhythmia

Pacemaker activity of the heart is generated by a small group of cells forming the sinoatrial node (SAN). Cells of the SAN are spontaneously active and generate action potentials with remarkable regularity and stability under all physiological conditions. The exact molecular mechanisms underlying pacemaker potentials in the SAN have not yet been fully elucidated. Several voltage-dependent ion channels as well as intracellular calcium cycling processes are thought to contribute to the pacemaker activity. Hyperpolarization-activated cation channels, which generate the I_f current, have biophysical properties which seem ideally suited for the initiation of spontaneous electrical activity. This review describes recent work on several transgenic mice lacking different cardiac HCN channel subtypes. The role of I_f for normal pacemaking and sinus node arrhythmia as revealed by these genetic models will be discussed. In addition, a new mouse line is described which enables gene targeting in a temporally-controlled manner selectively in SAN cells. Elucidating the function of HCN and other ion channels in well-controlled mouse models should ultimately lead to a better understanding of the mechanisms underlying human sinoatrial arrhythmias.