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

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Sarcoplasmic reticulum (SR) Ca<sup>2+</sup> cycling, that is, the Ca<sup>2+</sup> 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<sup>2+</sup> and membrane clocks. In pacemaker cells the intracellular Ca<sup>2+</sup> clock is manifested by spontaneous, rhythmic submembrane local Ca<sup>2+</sup> releases from SR, which are tightly controlled by a high degree of basal and reserve PKA-dependent protein phosphorylation. The Ca<sup>2+</sup> releases rhythmically activate Na<sup>+</sup>/Ca<sup>2+</sup> 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<sup>2+</sup> clock. The idea that spontaneous SR Ca<sup>2+</sup> 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.<br>

収録刊行物

  • Journal of pharmacological sciences  

    Journal of pharmacological sciences 100(5), 338-369, 2006-05-15 

    The Japanese Pharmacological Society

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各種コード

  • NII論文ID(NAID)
    10018238109
  • NII書誌ID(NCID)
    AA11806667
  • 本文言語コード
    ENG
  • 資料種別
    REV
  • ISSN
    13478613
  • NDL 記事登録ID
    7963150
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  CJP引用  NDL  J-STAGE 
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