The Integration of Spontaneous Intracellular Ca²⁺ Cycling and Surface Membrane Ion Channel Activation Entrains Normal Automaticity in Cells of the Heart's Pacemaker

Abstract

Although the ensemble of voltage- and time-dependent rhythms of surface membrane ion channels, the membrane "Clock", is the immediate cause of a sinoatrial nodal cell (SANC) action potential (AP), it does not necessarily follow that this ion channel ensemble is the formal cause of spontaneous, rhythmic APs. SANC also generates intracellular oscillatory spontaneous Ca(2+) releases that ignite excitation (SCaRIE) of the surface membrane via Na(+)/Ca(2+) exchanger activation. The idea that a rhythmic intracellular Ca(2+) Clock might keep time for normal automaticity of SANC, however, has not been assimilated into mainstream pacemaker dogma. Recent experimental evidence, derived from simultaneous, confocal imaging of submembrane Ca(2+) and membrane potential of SANC, and supported by numerical modeling, indicates that normal automaticity of SANC is entrained and stabilized by the tight integration of the SR Ca(2+) Clock that generates rhythmic SCaRIE, and the surface membrane Clock that responds to SCaRIE to immediately produce APs of an adequate shape. Thus, tightly controlled, rhythmic SCaRIE does not merely fine tune SANC AP firing, but is the formal cause of the basal and reserve rhythms, insuring pacemaker stability by rhythmically integrating multiple Ca(2+)-dependent functions, and effects normal automaticity by rhythmic ignition of the surface membrane Clock.

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

“…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).…”

What makes the heart rhythm so intricate?

“…In previous work, Lakatta et al established the "Ca 2+ clock" as a pacemaking mechanism that parallels the classical "membrane clock". 10 The Ca 2+ clock is based on spontaneous diastolic stochastic Ca 2+ release events from the sarcoplasmic reticulum, which enhance depolarization via the Na + /Ca 2+ exchange current. These Ca 2+ release events are potentiated by β-adrenergic stimulation.…”

“…These Ca 2+ release events are potentiated by β-adrenergic stimulation. 10 Because every myocyte contains thousands of interacting Ca 2+ release units, the question whether spatial interactions between Ca 2+ release units within a single cell may contribute to fractal BRV patterns is therefore pertinent. This hypothesis is supported by the recent study of Nivala et al, 11 who investigated Ca 2+ release patterns emerging in a threedimensional model of the myocyte comporting 20000 interacting Ca 2+ release units.…”