What keeps us ticking: a funny current, a calcium clock, or both?

Abstract

The processes underlying the initiation of the heartbeat, whether due to intracellular metabolism or surface membrane events, have always been a major focus of cardiac research. About 50 years ago, a pioneering work initiated by Silvio Weidmann and others applied the Hodgkin–Huxley formalism of membrane excitation to interpret the cardiac electrical activity, including the pacemaker depolarization (see D. Noble, 1979. The initiation of the heartbeat, Clarendon Press). The underlying idea was that voltageand time-dependent gating of various surface membrane channels not only generated the cardiac pacemaker action potential (AP), but also controlled the spontaneous depolarization between AP's and thus determinedwhen thenextAPwouldoccur. According to this description, the ensemble of surface membrane ion channels works as a clock that regulates the rate and rhythm of spontaneous AP firing, otherwise known as normal automaticity. A formidable research effort then concentrated in attempting to target which of the surface membrane ion channels had an important role in controlling the spontaneous diastolic depolarization (DD). Originally, a major role was attributed to the “IK-decay theory”. This was strongly influenced by the previous Hodgkin–Huxley model of nerve AP, which described the slow depolarization following a nerve AP as due to the decay of a K current. This model of pacemaker depolarization lasted some 20 years, until it was turned upside-down by a full re-interpretation based on the discovery of the If current. Other ionic currents gated by membrane depolarization, i.e. ICaL, ICaT, IST, non-gated and non-specific background leak currents, and also a current generated by the Na–Ca exchange (NCX) carrier, were also proposed to be involved in pacemaking. Based on a wealth of experimental evidence, If is today considered as the most important ion channel involved in the rate regulation of cardiac pacemaker cells, and is sometimes referred to as “the pacemaker channel.” Several studies, some of which recent, have also shown that in addition to voltage and time, surface membrane electrogenic molecules are strongly modulated by Ca and phosphorylation. The studies of a sub-group of pacemaker cell researchers focusing Journal of Molecular and Cellular Cardiology 47 (2009) 157–170