Mechanism of muscarinic control of the high-threshold calcium current in rabbit sino-atrial node myocytes

Petit-Jacques, Jérôme; Bois, Patrick; Bescond, Jocelyn; Lenfant, J

doi:10.1007/bf00374956

Cited by 71 publications

(87 citation statements)

References 40 publications

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“…Ionic basis of the effects of vagal stimulation ACh, released from vagal nerves, is known to activate the muscarinic K+ current (iK,ACh) and decrease the Ca2+ current (ica) and the hyperpolarization-activated current (if) (e.g. DiFrancesco, Ducouret & Robinson, 1989;Honjo, Kodama, Zang & Boyett, 1992;Petit-Jacques, Bois, Bescond & Lenfant, 1993). In the presence of a fl-agonist, ACh also decreases a Cl-current (Tareen, Ono, Noma & Ehara, 1991).…”

Section: Discussionmentioning

confidence: 99%

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

Kodama

Boyett

Suzuki

et al. 1996

The Journal of Physiology

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1. The effects of brief postganglionic vagal nerve stimulation on electrical activity in different regions of the rabbit sino-atrial node and surrounding atrial muscle were recorded. 2. At the centre of the node (the leading pacemaker site), the brief stimulation resulted in a large hyperpolarization followed by a depolarization and a shortening of the action potential. All effects were short lasting (time to 90% recovery of membrane potential, 0 8 s). 3. At other sites within the node and in the surrounding atrial muscle, although there was still a substantial action potential shortening, the hyperpolarization was smaller and the depolarization was small or absent. All effects were longer lasting (time to 90 % recovery in atrial muscle, 11 4 s). 4. The depolarization in the centre of the node was abolished by block of the hyperpolarizationactivated current (if) by Cs+ or zatebradine (UL-FS 49). It could, therefore, result from the activation of if during the preceding hyperpolarization. 5. Block of acetylcholinesterase by eserine greatly slowed recovery from vagal stimulation at all sites, demonstrating that recovery is dependent on acetylcholinesterase. The longer lasting effects of vagal stimulation in atrial muscle, therefore, result from lower acetylcholinesterase activity. 6. Vagal stimulation resulted in a short-lasting initial slowing of spontaneous action potentials followed by a long-lasting secondary slowing. Whereas the initial slowing coincided with the effects of vagal stimulation on the centre of the node, the secondary slowing coincided with the slower effects of vagal stimulation on the surrounding atrial muscle. The secondary slowing was reduced by 68 + 11 % (n = 5) by cutting the atrial muscle away from the node. 7. It is concluded that the short-lasting initial slowing of spontaneous action potentials is the direct effect of vagal stimulation on the centre of the sino-atrial node, whereas the secondary slowing is the result of the longer lasting effects of vagal stimulation on the surrounding atrial muscle and the electrotonic suppression of the node by the muscle.

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Section: Discussionmentioning

confidence: 99%

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

Kodama

Boyett

Suzuki

et al. 1996

The Journal of Physiology

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“…Among proteins highly phosphorylated in the basal state are phospholamban (Fig. 5) and RyRs [5]; and indirect evidence suggests that L-type Ca 2+ channels are likely to be as well [18]. PKA dependent phosphorylation of these proteins presents the SR with an increased Ca 2+ to be pumped (Ca 2+ influx via I CaL ), speeds up the SR Ca 2+ filling rate (phospholamban), and likely alters the Ca 2+ release threshold (ryanodine receptors).…”

Section: Spontaneous Lcrs Are Rhythmic: the Sr Is A "Ca 2+ Clock"mentioning

confidence: 99%

“…10B). This effect of de-phosphorylation also likely involves graded effects on L-type Ca 2+ channels [18] to reduce Ca 2+ influx and cytosolic Ca 2+ , and on SR Ca 2+ cycling proteins to decelerate Ca 2+ cycling. In slowing the basal SR Ca 2+ Clock and prolonging the LCR period ( Fig.…”

Section: Slowing Of the Ca 2+ Clock By Pka-inhibitionmentioning

confidence: 99%

“…Ca 2+ influx via I CaL (and, possibly, via reverse NCX function) also "refuels" the Ca 2+ clock by supplying Ca 2+ to be pumped into the SR. The basal, sustained SANC Ca 2+ clock function is supported not only by enhanced function of SR Ca 2+ cycling proteins but also results from an enhanced L-type Ca 2+ channel activity, as these channels seem to be highly phosphorylated in the basal state by PKA [18]. In general, modulatory changes of ion channel characteristics produced by Ca 2+ , cAMP, and cAMP/PKAdependent phosphorylation (see review [2] for details) can be viewed as supporting the enhanced Ca 2+ clock operation (dotted lines in Fig.…”

Section: Membrane Ion Channels and Transporters Regulate The Intracelmentioning

confidence: 99%

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

Maltsev

Lakatta

2007

Heart, Lung and Circulation

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For almost half a century it has been thought that the heart rhythm originates on the surface membrane of the cardiac pacemaker cells and is driven by voltage-gated ion channels (membrane clocks). Data from several recent studies, however, conclusively show that the rhythm is initiated, sustained, and regulated by oscillatory Ca 2+ releases (Ca 2+ clock) from the sarcoplasmic reticulum, a major Ca 2+ store within sinoatrial node cells, the primary heart's pacemakers. Activation of the local oscillatory Ca 2+ releases is independent of membrane depolarization and driven by a high level of basal state phosphorylation of Ca 2+ cycling proteins. The releases produce Ca 2+ wavelets under the cell surface membrane during the later phase of diastolic depolarization and activate the forward mode of Na + / Ca 2+ exchanger resulting in inward membrane current, which ignites an action potential. Phosphorylation-dependent gradation of speed at which Ca 2+ clock cycles is the essential regulatory mechanism of normal pacemaker rate and rhythm. The robust regulation of pacemaker function is insured by tight integration of Ca 2+ and membrane clocks: the action potential shape and ion fluxes are tuned by membrane clocks to sustain operation of the Ca 2+ clock which produces timely and powerful ignition of the membrane clocks to effect action potentials.

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“…It turned out that in contrast to rabbit ventricular myocytes, Ca 2+ cycling proteins, e.g. phospholamban, ryanodine receptors, and likely L-type Ca 2+ channels in rabbit SANC, are highly phosphorylated in the basal state [27](for L-type Ca 2+ channels see [28]). PKA-dependent phosphorylation of these proteins presents the SR with an increased Ca 2+ to be pumped (Ca 2+ influx via I CaL ), speeds up the SR Ca 2+ filling rate (phospholamban), and alters the Ca 2+ release threshold (ryanodine receptors).…”

Section: How Cell Ca 2+ Cycling Links To Ncx Function and Why It Is Cmentioning

confidence: 99%

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

Maltsev

Lakatta

2007

Journal of Molecular and Cellular Cardiology

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Cardiac ischemia is an important global health problem. It leads to contraction failure, arrhythmias, and cardiac cell death. Sinus bradycardia characterized by a slow heart rate (<60 bpm) is a prominent ischemia-related arrhythmia directly caused by a deficiency of heart beat initiation within the sinoatrial node (SAN), due to a failure of the heart's primary pacemaker cells (SANC). The study presented by Yi-Mei Du and Richard Nathan in this issue of Journal of Molecular and Cellular Cardiology [1] deals with the ionic basis of ischemia-induced bradycardia in isolated SANC. The results of their study not only contribute to understanding of ischemia-induced bradycardia, but also help to delineate the fundamental mechanisms of cardiac pacemaker cell function. Study design and hypothesisIn their studies, Du and Nathan simulated ischemia by superfusing SANC with a solution without glucose, at pH 6.6 that contained either 5.4 or 10 mM KCl. This lead, to a 13% or 43% reduction, respectively, in the spontaneous beating rate of freshly isolated SANC. This simulated ischemia is not true ischemia, e.g. there is no associated hypoxia or flow deficiency effects other than elevated [K + ]. Nonetheless simulated ischemia of this sort is often applied in studies like the present one. And, in their careful approach to the problem, the authors first demonstrated that their "ischemic" solutions produced bradycardia in the intact rabbit heart. Then, in isolated SANC they measured the effects of this simulated ischemia on membrane potential and ion currents under voltage clamp. Such an approach is not surprising, because it has been believed for almost half a century that the heart rhythm originates on the surface membrane of the cardiac pacemaker cells. This dogma stems from the Nobel prize triumph of the Hodgkin-Huxley neuron membrane excitability theory [2] and subsequent modification of this theory and extrapolation to the heart cells by Noble (1960) [3]. According to this theory, generation of spontaneous action potentials (APs) by cardiac pacemaker cells is portrayed as a membrane delimited process, i.e. by a pure interplay of time-and voltage-dependent ion currents. Pacemaker field researchers have focused mainly on the identification of multiple ion current components in pacemaker cells, and their respective roles in the spontaneous diastolic depolarization of these cells (DD, Fig.1A) that brings the membrane to the excitation threshold (reviews [4,5]). Du and Nathan thus tested an hypothesis that bradycardia induced by their

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Mechanism of muscarinic control of the high-threshold calcium current in rabbit sino-atrial node myocytes

Cited by 71 publications

References 40 publications

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

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

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

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