The Emergence of a General Theory of the Initiation and Strength of the Heartbeat

Abstract

Abstract. Sarcoplasmic reticulum (SR) Ca2+ cycling, that is, the Ca 2+ clock, entrained by externally delivered action potentials has been a major focus in ventricular myocyte research for the past 5 decades. In contrast, the focus of pacemaker cell research has largely been limited to membrane-delimited pacemaker mechanisms (membrane clock) driven by ion channels, as the immediate cause for excitation. Recent robust experimental evidence, based on confocal cell imaging, and supported by numerical modeling suggests a novel concept: the normal rhythmic heart beat is governed by the tight integration of both intracellular Ca 2+ and membrane clocks. In pacemaker cells the intracellular Ca 2+ clock is manifested by spontaneous, rhythmic submembrane local Ca 2+ releases from SR, which are tightly controlled by a high degree of basal and reserve PKA-dependent protein phosphorylation. The Ca 2+ releases rhythmically activate Na + / Ca 2+ exchange inward currents that ignite action potentials, whose shape and ion fluxes are tuned by the membrane clock which, in turn, sustains operation of the intracellular Ca 2+ clock. The idea that spontaneous SR Ca 2+ releases initiate and regulate normal automaticity provides the key that reunites pacemaker and ventricular cell research, thus evolving a general theory of the initiation and strength of the heartbeat.

Cardiac pacemaker cell failure with preserved If, ICaL, and IKr: A lesson about pacemaker function learned from ischemia-induced bradycardia

“…Furthermore, because NCX is activated by intracellular Ca 2+ , a broad interpretation of the results of this study is that pacemaker failure during simulated ischemia is not caused solely by ion channel failure, but also by altered SR Ca 2+ cycling and/or a compromised intracellular Ca 2+ integration with the membrane excitation due to the deficiency of NCX function. This interpretation supports the novel hypothesis [7] that normal cardiac pacemaker function requires functional integration of internal Ca 2+ cycling with membrane-delimited electrogenic proteins. According to this Ca 2+ integrated pacemaker concept, spontaneous local Ca 2+ releases emerging during the late DD activate an ensemble of local inward NCX currents; this accelerates DD and ignites I CaL to generate an AP (Fig.…”

“…This major divergence of the DD from its normal shape thus ought to be produced by the reduction of I NCX found by Du and Nathan in the ischemic solution. The corollary of the demonstration that I NCX is markedly reduced by simulated ischemia is that I NCX must be also critical to normal pacemaker function, thus providing a new additional piece of evidence for the fundamental importance of the NCX for SANC function suggested previously by different research groups [7,17,23].…”

“…T-and L-type Ca 2+ currents and Na + /Ca 2+ exchange (NCX) current (I CaT , I CaL I NCX , respectively, Fig.1A, "Inward currents"). A plethora of recent data has emerged to conclusively show that intracellular Ca 2+ dynamics, in tight cooperation with surface membrane proteins, are critical for the normal spontaneous firing of SANC (reviews [6,7]). Nathan's group, in fact, was among the pioneers that discovered the major role of intracellular Ca 2+ cycling in pacemaker function, showing that ryanodine, which interferes with Ca 2+ release from the sarcoplasmic reticulum (SR), and BAPTA-AM, which chelates intracellular Ca 2+ , significantly slowed the spontaneous beating rate of cardiac pacemaker cells [8][9][10] The forth inward current measured was the "funny" current (I f ) activated by membrane hyperpolarization, often referred to as "the" pacemaker current [11,12].…”

“…Ca 2+ cycling in cardiac cells is characterized by two major types of Ca 2+ releases from SR: global, AP-synchronized Ca 2+ transients and spontaneous, local Ca 2+ releases (LCRs) (recent reviews [6,7]). The essence of Ca 2+ cycling in normal ventricular muscle cells is the Ca 2+ transient, which is initiated and entrained by externally delivered APs, and serves as a high gain signal amplifier within Ca 2+ -induced-Ca 2+ -relase (CICR) paradigm.…”

“…While the Ca 2+ clock keeps the time of the SANC pacemaker, it is tightly integrated with the plasma membrane proteins (including both electrogenic process and Ca 2+ transport) resulting in an extremely robust pacemaker operation [6,7]: Rhythmic LCRs excite the cell surface membrane via activation of inward NCX current during the late DD phase, but AP-induced Ca 2+ influx in turn, depletes SR Ca 2+ content (Fig.1A, Ca 2+ Clock "reset") via CICR; and it also balances the NCX-related Ca 2+ efflux ("refueling" Ca 2+ Clock).…”