Ionic channels underlying cardiac automaticity: new insights from genetically-modified mouse strains.

The spontaneous activity (or pacemaker activity) of the heart constitutes a fundamental physiological function in higher organisms. Pacemaker activity is generated in the sino-atrial node (SAN) by a specialized cell population adapted to the generation of a rhythmic electrical oscillation. The precise ionic mechanisms underlying initiation of pacemaking in automatic cells has not been entirely elucidated. Ionic channels and intracellular Ca2+ signalling in pacemaker cells are both required for the proper setting of pacemaking. Understanding the mechanisms of pacemaker activity is important for developing new therapeutic approaches for controlling the heart rate in the diseased myocardium. Controlling the heart rate in the clinical practice is a promising way to increase cardioprotection and improve patient's survival in cardiac ischemic pathology. We describe here the contribution of several ion channels families into the generation and regulation of the heart rate using new approaches involving genetically modified mouse strains. These studies underline the functional redundancy of mechanisms underlying pacemaking, an important safety parameter for new drugs targeting ion channels to modulate cardiac frequency.