Normal Heart Rhythm is Initiated and Regulated by an Intracellular Calcium Clock Within Pacemaker Cells

Maltsev, Victor A.; Lakatta, Edward G.

doi:10.1016/j.hlc.2007.07.005

Cited by 58 publications

(56 citation statements)

References 40 publications

(90 reference statements)

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“…Evidence for a functional interaction between the ryanodine receptor-mediated Ca 2+ release and the cardiac isoform of the NCX-1 Na + -Ca 2+ exchanger [89][90][91] gave rise to an alternative theory, "the calcium clock", in which diastolic spontaneous Ca 2+ release activates the Na + -Ca 2+ NCX-1 exchanger in its forward mode. In these conditions, the net electrogenic inward current resulting from the entrance of 3 Na + and the extrusion of 1 Ca 2+ depolarizes the membrane of the cell toward the threshold and generates an action potential [92,93] (Figure 3, right panel). RyR2 and NCX-1 can be modulated by adrenergic stimulation.…”

Section: Calcium Clock Modelmentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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Section: Calcium Clock Modelmentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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“…Diastolic SR Ca 2ϩ release contributes to ISO-mediated increases in DDR by augmenting inward Na ϩ /Ca 2ϩ exchanger current (I NCX ) (16,17) as part of a ''Ca 2ϩ clock'' fight or flight cellular mechanism for increasing HR (18). We simultaneously measured cell membrane potential and Ca i 2ϩ in spontaneously beating SAN cells loaded with the Ca 2ϩ indicator Rhod-2 acetoxymethyl ester using confocal line scan imaging at baseline and with ISO ( Fig.…”

Section: Increased Phase 4 Depolarization By Iso Requiresmentioning

confidence: 99%

Calmodulin kinase II is required for fight or flight sinoatrial node physiology

Wu¹,

Gao²,

Chen³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

129

175

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The best understood ''fight or flight'' mechanism for increasing heart rate (HR) involves activation of a cyclic nucleotide-gated ion channel (HCN4) by ␤-adrenergic receptor (␤AR) agonist stimulation. HCN4 conducts an inward ''pacemaker'' current (If) that increases the sinoatrial nodal (SAN) cell membrane diastolic depolarization rate (DDR), leading to faster SAN action potential generation. Surprisingly, HCN4 knockout mice were recently shown to retain physiological HR increases with isoproterenol (ISO), suggesting that other I f-independent pathways are critical to SAN fight or flight responses. Here, we show that CaMKII plays a previously unanticipated but decisive role to increase SAN rates during ␤AR stimulation. Studies in hearts from mice with SAN cell CaMKII inhibition suggest that CaMKII activity is required for chronotropic responses to ISO. CaMKII is selectively engaged in SAN cells during ␤AR stimulation and leads to coordinated enhancement of SR Ca 2ϩ filling, greater diastolic SR Ca 2ϩ release, and an increased diastolic depolarization rate (DDR) to increase HRs, independent of I f . In contrast, CaMKII inhibition does not slow HRs or SAN cell action potential (AP) frequency in the absence of ␤AR stimulation or when SR Ca 2ϩ release is disabled. These studies define a novel, CaMKII-dependent cellular mechanism for SAN fight or flight physiology.

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“…Transfection of an enzyme that metabolizes IP 3 , and thereby prevents its Ca 2+ -mobilising action, or an anti-IP 3 R antibody, inhibited the spontaneous activity [97]. In the sinus node of the adult mammalian heart, spontaneously active pacemaker cells make use of cyclic subsarcolemmal RyR-mediated SR Ca 2+ release to activate depolarizing NCX current, which contributes to diastolic depolarization and pacemaker activity (for review see [160]). This 'intracellular Ca 2+ clock' is fueled by high, cAMP-dependent Ca 2+ turnover.…”

Section: Ip 3 Rs In Other Cardiac Cellsmentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

169

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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Normal Heart Rhythm is Initiated and Regulated by an Intracellular Calcium Clock Within Pacemaker Cells

Cited by 58 publications

References 40 publications

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

Calmodulin kinase II is required for fight or flight sinoatrial node physiology

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

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