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, 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 “I_K-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 I_f current. Other ionic currents gated by membrane depolarization, i.e. I_CaL, I_CaT, I_ST, 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, I_f 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 I_f 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 occur during the DD and activate NCX, causing the late DD to exponentially increase, driving the membrane potential to the threshold for the rapid upstroke of the next AP. Such rhythmic, spontaneous intracellular Ca²⁺ cycling has been referred to as an “intracellular Ca²⁺ clock”, i.e. a component that interacts with the classic sarcolemmal membrane voltage clock to form the overall pacemaker clock.

Needless to say, there is presently some degree of uncertainty about the relative roles of I_f vs that of intracellular Ca²⁺ cycling in controlling the normal pacemaker cell automaticity. The dialogue that ensues aims to present and refute both sides of the issue. Sit back and enjoy the show!

Fig. 1

Schematic illustration of the interplay of Ca²⁺, basal Ca²⁺ -activated AC, cAMP, PDE activity and PKA and CaMKII activity, cast in the context of sarcoplasmic reticulum Ca²⁺ cycling, L-type Ca²⁺ channels, and other ion channels. Spontaneous but rhythmic local submembrane Ca²⁺ releases during the later DD activate I_NCX, causing the DD to increase exponentially to achieve the threshold for I_CaL activation and the generation of the next AP. See text for further details. (adapted from [83]).

Fig. 2

Action potentials recorded from rabbit SAN pacemaker cells in control conditions and in the presence of ivabradine 0.3 µM or ryanodine 3 µM (top) are compared with action potentials recorded before and during perfusion with the autonomic agonists Iso 1 µM or ACh 0.3 µM (bottom). Autonomic agonists modify rate by changing the slope of DD, including the early fraction, like ivabradine, while ryanodine affects mostly the late fraction of DD (partly adapted from [131]).