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

Abstract

Prologue 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, 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 voltage- and 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 determined when the next AP would occur. 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 Ca2+ and phosphorylation. The studies of a sub-group of pacemaker cell researchers focusing upon intracellular Ca2+ movements in pacemaker cells spawned the idea that intracellular Ca2+ is an important player in controlling pacemaker cell automaticity. This elevated the status of NCX current as a major Ca2+-activated electrogenic mechanism. But the fine details of intracellular Ca2+ movements, specifically those beneath the cell membrane during DD, were not at hand, and the concept of Ca2+ involvement in pacemaking stalled, whilst the concept of If control continued to soar—expanding to the design of novel drug development and biological pacemakers. More recent discoveries over the past decade, made possible by simultaneous submembrane Ca2+ imaging and membrane potential or current recordings with cell-attached patch electrodes, have shown that critically timed Ca2+ releases ...

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

“…A critical role for PDE4 has also been suggested in human heart based on the observations that inhibition of PDE4 in atrial myocytes increases Ca spark frequency and initiates spontaneous Ca waves [74], and that the PDE4D isoform immunoprecipitates with the cardiac RyR2 channel in heart extracts [75]. In the "intracellular Ca clock" model of cardiac pacemaking, such tight relationship between PDE4, RyR2, and Ca spark frequency would ensure a crucial role for PDE4 in controlling heart rate [76]. Nevertheless, it is surprising that PDE3 inhibitors do not produce more effect [77], but it is possible that the subcellular compartmentalization of cAMP pools is sufficient to insulate PDE3 inhibition from pacemaker mechanisms [78]; the observation that the more prolonged inhibition of PDE3 can lead to small increases in beating frequency would support the compartmentalization idea.…”

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

“…Finally, pharmacological approaches using high concentrations of ryanodine on the entire SAN from wild-type rabbit only moderately decreased its pacing rate [105] . Taken together, the membrane clock and calcium clock models are still highly debated [106] and raise many counterpoints and paradoxes. New theories that integrate both models are emerging [107][108][109] , but it remains challenging to provide a clear answer to the simple question that was asked more than a century ago.…”

Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4

“…funny current | heart rate | sinoatrial node | atrioventricular node | chronotropism T he degree of complexity of the processes involved in pacemaking and their individual contributions is still a hotly debated issue (1,2). Despite this complexity, and granting the fact that perturbation of any participating mechanism can affect rate, there is evidence for a functional specificity of "funny" (f)-channels in mediating generation and physiological control of pacemaker activity.…”