Progress in the Intracellular Clock that Drives the Heart's Pacemaker

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LCS studies of pacemaker function have generated the idea that, as reviewed here, normal automaticity of SANC results from the mutual entrainment of an internal Ca2+ clock and surface membrane ion channel clock. In short, The Ca2+ clock in rabbit SANC is driven by high basal level of cAMP. Constitutive activation of b-ARs is not present within SANC. Rather, SANC express AC isoforms that are Ca2+ activated (AC1&8), permitting Ca2+ releases to act as a feed forward system to control SANC beating: Ca2+ activation of AC increases cAMP which activates PKA resulting in phosphorylation of Ca2+ cycling proteins and an acceleration of the Ca2+ clock. A markedly elevated basal PDE activity within SANC acts as brake to limit the cAMP level and the extent of cAMP-dependent phosphorylation of Ca2+ cycling proteins regulates LCRs characteristics and maintains basal beating rate well below maximum level. In other words, PKA dependent phosphorylation regulates kinetics of SR Ca2+ cycling and also determines the constitutive activity of ACs (activated by Ca2+), which, in turn, increases cAMP and PKA and thus determines the periodicity of LCRs, which in turn, determines the spontaneous SANC cycle length. Graded inhibition of PKA activity results in graded reduction of Ca2+ cycling protein phosphorylation, graded slowing of the Ca2+ clock (prolongation of LCR period) and graded reduction of the spontaneous beating rate 4.As noted, evidence regarding control of basal cAMP mediated PKA dependent Ca2+ cycling protein phosphorylation that drives spontaneous beating of SANC has begun to emerge. Based on our extensive database presented here, we suggest a new, relatively simple interpretation of the entire DD shape, a major problem of the cardiac pacemaker field since its discovery. The Ca2+ clock initiates each pacemaker cycle by igniting a subsequent AP via DD acceleration. The MDP, followed by early slow DD, are in fact components of an afterpotential, i.e. recovery of ion channels from previous AP. The evidence for the crucial role of Ca2+ and rhythmic spontaneous Ca2+ releases in the initiation and regulation of normal cardiac automaticity both in adult and embryonic pacemaker cells also provides the key that reunites pacemaker and ventricular cell research 32, 35. The separate achievements of reductionist approaches to elucidate how strength of contraction of ventricular myocytes and the spontaneous beating rate of pacemaker cells are regulated now converge: Ca2+ cycling into and from the SR by proteins common to both ventricular myocytes and pacemaker cells can be portrayed as Ca2+ clock. The mutual entrainment of the Ca2+ clock and surface membrane ion channel clocks regulate the duty cycle of both cell types. THUS, BASED UPON OUR STUDIES, WE PROPOSE A GENERAL THEORY OF CARDIAC INOTROPY AND CHRONOTROPY.