Competing Oscillators in Cardiac Pacemaking

Noble, Denis; Noble, Penelope J.; Fink, Martin

doi:10.1161/circresaha.110.218875

Cited by 33 publications

(32 citation statements)

References 30 publications

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“…HCN4, a pore-forming subunit that is responsible for the pacemaker current I f , is commonly used to distinguish nodal from chamber myocardium (2). Pacemaking is accomplished by a network of ion channels (M-clock) that act together to generate the pacemaker potential and also involves intracellular Ca 2+ oscillations (Ca 2+ -clock) (5)(6)(7). Activation of the β-adrenergic receptor leads to the positive chronotropic effect of catecholamines on cardiac automaticity.…”

Section: Introductionmentioning

confidence: 99%

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Froese

Breher²,

Waldeyer³

et al. 2012

J. Clin. Invest.

137

455

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Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Froese

Breher²,

Waldeyer³

et al. 2012

J. Clin. Invest.

137

455

View full text Add to dashboard Cite

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“…As we discussed above, in contrast to the asymmetric nature of the pacemaker’s coupled oscillators based upon 1984 model simulations detailed by Noble et al (94), recent numerical modeling (10) of experimental data points to the idea that the cardiac pacemaker cell is, in fact, a system of symmetrically entrained, inter-dependent oscillators. In other words, during spontaneous AP firing, on a cycle-to-cycle basis, the Ca 2+ oscillator entrains the membrane oscillator by generating spontaneous rhythmic NCX current, prompting the generation of the next AP; but in doing so, loses Ca 2+ (its “fuel”) via Ca 2+ efflux by NCX.…”

Section: Controversies Unsolved Problems and Their Possible Solutmentioning

confidence: 83%

“…In their recent article “Competing oscillators in cardiac pacemaking: historical background” (94), Noble et al, while accepting the idea that mutual entrainment of the intracellular Ca 2+ oscillator and surface membrane oscillator (Ca 2+ clock and M-clock in our terminology) controls normal automaticity of the heart’s pacemaker cells, attempted to make the case that these oscillators are asymmetric. Specifically, the authors claim that the surface membrane voltage oscillator operates independently of the intracellular SR Ca 2+ oscillator.…”

Section: Controversies Unsolved Problems and Their Possible Solutmentioning

confidence: 99%

“…Nonetheless, in their review (94) Noble et al insist that NCX current in the 1984 model simulations is indeed activated during DD prior to activation of voltage-gated L-type Ca 2+ current. A careful examination of their Figure 2 in that paper, however, reveals that, in contrast to the experimental result at −44 mV (left top panel) of Brown et al(95), the model-simulated NCX current (right bottom panel) appears only at a much higher voltage (about −30 to −28 mV, dashed lines), i.e.…”

Section: Controversies Unsolved Problems and Their Possible Solutmentioning

confidence: 99%

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Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

et al. 2014

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Cardiac pacemaking is a complex phenomenon that is still not completely understood. Together with experimental studies, numerical modeling has been traditionally used to acquire mechanistic insights in this research area. This review summarizes the present state of numerical modeling of the cardiac pacemaker, including approaches to resolve present paradoxes and controversies. Specifically we discuss the requirement for realistic modeling to consider symmetrical importance of both intracellular and cell membrane processes (within a recent “coupled-clock” theory). Promising future developments of the complex pacemaker system models include the introduction of local calcium control, mitochondria function, and biochemical regulation of protein phosphorylation and cAMP production. Modern numerical and theoretical methods such as multi-parameter sensitivity analyses within extended populations of models and bifurcation analyses are also important for the definition of the most realistic parameters that describe a robust, yet simultaneously flexible operation of the coupled-clock pacemaker cell system. The systems approach to exploring cardiac pacemaker function will guide development of new therapies, such as biological pacemakers for treating insufficient cardiac pacemaker function that becomes especially prevalent with advancing age.

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“…The reader interested in the studies of cardiac rhythms described in terms of competing membrane oscillators can consult a very recent review by Noble et al [51] in which this interaction is described in terms of voltagedependent ion channels and an intracellular calcium signal oscillator. In turn, Imtiaz et al [52] have reviewed the synchronization of Ca 2+ oscillations with respect to a long-range signaling mechanism in smooth muscle that results in global outcomes of local interactions; the long-range electrochemical coupling was found to be many orders of magnitude stronger than the coupling through diffusion of Ca 2+ or inositol 1,4,5-triphosphate (Ins(1,4,5)P 3 ).…”

Section: Biochemical Membrane Oscillatorsmentioning

confidence: 99%

Liquid Membrane and Other Membrane Oscillators

Orlik

2012

Self-Organization in Electrochemical Systems II

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In complement to the hydrodynamic instabilities driven by surface tension gradients, enclosed in Sects. 5.4-5.7, we describe here the dynamics of the liquid-liquid interface, formed by two fluids of very limited miscibility, e.g., by water and 2-nitropropane. First reports on this type of dynamical systems have been published by Dupeyrat and Nakache [1,2], and later analogous studies were continued also by .A representative example of that type of the systems is the water-2-nitropropane system [3]. The key point is that each phase should contain the dissolved species that is significantly better soluble in the other phase. In this way the initial state of such system is far from equilibrium and the natural trend to decrease the free Gibbs energy is the flow of each dissolved species to the other phase. In the example described here, the aqueous phase contains initially the hexadecyltrimethylammonium bromide (or cetyltrimethylammonium bromide, CTAB) the large organic CTA + cation of which exhibits, due to its hydrophobicity, higher affinity to the organic phase. In turn, the phase of 2-nitropropane contains initially dissolved picric acid (HA), better soluble and also partly dissociating in water (pK a % 0.2).When these two phases are brought into contact, with the organic layer placed over the aqueous layer, the oppositely directed flows of CTAB and HPi begin. This transport is associated with subtle oscillations of various characteristics: pH of aqueous solution, interfacial potential drop (Fig. 6.1), and interfacial tension. The latter phenomena are easily detectable as visible oscillations of the meniscus at the interface of both liquids. It is interesting that under such non-equilibrium conditions the presence of surfactant (CTAB) does not depress the surface tension gradients, but on the contrary, it is responsible for their periodic temporal variations.Yoshikawa and Matsubara [3] have proposed the mechanism of these oscillatory phenomena. First, one should note that CTA + cations in both phases form micelles above certain critical CTA + concentrations. Those micelles exhibit inverted M. Orlik, Self-Organization in Electrochemical Systems II, Monographs in Electrochemistry,

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Competing Oscillators in Cardiac Pacemaking

Cited by 33 publications

References 30 publications

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

Liquid Membrane and Other Membrane Oscillators

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