scholarly journals Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells

2014 ◽  
Vol 143 (5) ◽  
pp. 577-604 ◽  
Author(s):  
Michael D. Stern ◽  
Larissa A. Maltseva ◽  
Magdalena Juhaszova ◽  
Steven J. Sollott ◽  
Edward G. Lakatta ◽  
...  
Keyword(s):  
Hierarchical Clustering ◽  
Calcium Release ◽  
Sinoatrial Node ◽  
Sinus Node ◽  
Ryanodine Receptors ◽  
Membrane Currents ◽  
Immunofluorescent Staining ◽  
Adrenergic Stimulation ◽  
Beating Rate ◽  
Sinoatrial Node Cells

The sinoatrial node, whose cells (sinoatrial node cells [SANCs]) generate rhythmic action potentials, is the primary pacemaker of the heart. During diastole, calcium released from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) interacts with membrane currents to control the rate of the heartbeat. This “calcium clock” takes the form of stochastic, partially periodic, localized calcium release (LCR) events that propagate, wave-like, for limited distances. The detailed mechanisms controlling the calcium clock are not understood. We constructed a computational model of SANCs, including three-dimensional diffusion and buffering of calcium in the cytosol and SR; explicit, stochastic gating of individual RyRs and L-type calcium channels; and a full complement of voltage- and calcium-dependent membrane currents. We did not include an anatomical submembrane space or inactivation of RyRs, the two heuristic components that have been used in prior models but are not observed experimentally. When RyRs were distributed in discrete clusters separated by >1 µm, only isolated sparks were produced in this model and LCR events did not form. However, immunofluorescent staining of SANCs for RyR revealed the presence of bridging RyR groups between large clusters, forming an irregular network. Incorporation of this architecture into the model led to the generation of propagating LCR events. Partial periodicity emerged from the interaction of LCR events, as observed experimentally. This calcium clock becomes entrained with membrane currents to accelerate the beating rate, which therefore was controlled by the activity of the SERCA pump, RyR sensitivity, and L-type current amplitude, all of which are targets of β-adrenergic–mediated phosphorylation. Unexpectedly, simulations revealed the existence of a pathological mode at high RyR sensitivity to calcium, in which the calcium clock loses synchronization with the membrane, resulting in a paradoxical decrease in beating rate in response to β-adrenergic stimulation. The model indicates that the hierarchical clustering of surface RyRs in SANCs may be a crucial adaptive mechanism. Pathological desynchronization of the clocks may explain sinus node dysfunction in heart failure and RyR mutations.

scholarly journals Diastolic Calcium Release Controls the Beating Rate of Rabbit Sinoatrial Node Cells: Numerical Modeling of the Coupling Process

2004 ◽  
Vol 86 (4) ◽  
pp. 2596-2605 ◽  
Author(s):  
Victor A. Maltsev ◽  
Tatiana M. Vinogradova ◽  
Konstantin Y. Bogdanov ◽  
Edward G. Lakatta ◽  
Michael D. Stern
Keyword(s):  
Numerical Modeling ◽  
Calcium Release ◽  
Sinoatrial Node ◽  
Coupling Process ◽  
Beating Rate ◽  
Sinoatrial Node Cells ◽  
Rabbit Sinoatrial Node

scholarly journals Decreased cardiac pacemaking and attenuated β-adrenergic response in TRIC-A knockout mice

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244254
Author(s):  
Manabu Murakami ◽  
Yuichi Toyama ◽  
Manabu Yonekura ◽  
Takayoshi Ohba ◽  
Yasushi Matsuzaki ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Rhythm ◽  
Calcium Release ◽  
Sinus Node ◽  
Ryanodine Receptors ◽  
Regulatory System ◽  
Adrenergic Stimulation ◽  
Physiological Importance ◽  
Cardiac Pacemaking ◽  
Sympathetic Responses

Changes in intracellular calcium levels in the sinus node modulate cardiac pacemaking (the calcium clock). Trimeric intracellular cation (TRIC) channels are counterion channels on the surface of the sarcoplasmic reticulum and compensate for calcium release from ryanodine receptors, which play a major role in calcium-induced calcium release (CICR) and the calcium clock. TRIC channels are expected to affect the calcium clock in the sinus node. However, their physiological importance in cardiac rhythm formation remains unclear. We evaluated the importance of TRIC channels on cardiac pacemaking using TRIC-A-null (TRIC-A–/–) as well as TRIC-B+/–mice. Although systolic blood pressure (SBP) was not significantly different between wild-type (WT), TRIC-B+/–, and TRIC-A–/–mice, heart rate (HR) was significantly lower in TRIC-A–/–mice than other lines. Interestingly, HR and SBP showed a positive correlation in WT and TRIC-B+/–mice, while no such correlation was observed in TRIC-A–/–mice, suggesting modification of the blood pressure regulatory system in these mice. Isoproterenol (0.3 mg/kg) increased the HR in WT mice (98.8 ± 15.1 bpm), whereas a decreased response in HR was observed in TRIC-A–/–mice (23.8 ± 5.8 bpm), suggesting decreased sympathetic responses in TRIC-A–/–mice. Electrocardiography revealed unstable R-R intervals in TRIC-A–/–mice. Furthermore, TRIC-A–/–mice sometimes showed sinus pauses, suggesting a significant role of TRIC-A channels in cardiac pacemaking. In isolated atrium contraction or action potential recording, TRIC-A–/–mice showed decreased response to a β-adrenergic sympathetic nerve agonist (isoproterenol, 100 nM), indicating decreased sympathetic responses. In summary, TRIC-A–/–mice showed decreased cardiac pacemaking in the sinus node and attenuated responses to β-adrenergic stimulation, indicating the involvement of TRIC-A channels in cardiac rhythm formation and decreased sympathetic responses.

Particular Sensitivity of the Mammalian Heart Sinus Node Cells

Physiology ◽  
1994 ◽  
Vol 9 (2) ◽  
pp. 77-79 ◽  
Author(s):  
J Petit-Jacques ◽  
J Bescond ◽  
P Bois ◽  
J Lenfant
Keyword(s):  
Adenylate Cyclase ◽  
Spontaneous Activity ◽  
Sinoatrial Node ◽  
Sinus Node ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Adrenergic Stimulation ◽  
Mammalian Heart ◽  
Ionic Mechanisms ◽  
Distinctive Property

High resting adenylate cyclase activity, implying a high basal adenosine 3', 5'-cyclic monophosphate level, seems to be a distinctive property of sinoatrial node cells of mammalian heart. This may explain why acetylcholine depresses two ionic mechanisms involved in spontaneous activity of nodal myocytes, via inhibition of adenylate cyclase activity, without previous b-adrenergic stimulation.

Abstract 202: Engineering Artificial Sinus Node by Reprogrammed Cardiomyocytes

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Hu Yufeng ◽  
Shih-Ann Chen
Keyword(s):  
Sinus Node ◽  
Neonatal Rat ◽  
Immunofluorescent Staining ◽  
Three Dimension ◽  
Over Expression ◽  
Pilot Model ◽  
Engineered Tissues ◽  
Beating Rate ◽  
Engineered Tissue ◽  
Supportive Cells

The lack of clinically relevant sinoatrial node (SAN) disease model makes the pathophysiological investigation and therapeutic development stagnant. We hypothesize that engineering SAN by TBX18 somatic-reprogrammed cardiomyocytes on the three-dimension (3D) scaffold could create an in vitro SAN model, sharing similar features with a native SAN. Methods: In addition to neonatal rat ventricular cardiomyocytes (NRVMs) alone, we chose cardiosphere-derived cells (CDCs), or fibroblasts as supportive cells with different mixing ratios to construct engineered SAN. Hydrogel scaffolds including matrigels or platelet gels were used and compared. The engineered tissue was reprogrammed by TBX18 over-expression. Results: The over-expression of TBX18 increased HCN4 and CX45 transcriptions in cardiomyocytes. A stable spontaneous beating rate could be created in TBX18-reprogrammed engineered tissue, made of NRVMs and fibroblasts with matrigel scaffold (beating rate, TBX18 vs. control: 105.0 ± 10.7 bpm vs. 35.5±7.1 bpm, n=12, P<0.001). Although spontaneous beating could be observed in reprogrammed engineered tissues by NRVM alone, NRVM with CDCs, or NRVMs with CDCs and fibroblasts, the beating rates were not stable and slower. The beating rate in engineered tissue did not differ between scaffolds of matrigel and platelet gel. However, inter-experimental variation is higher in platelet gels, compared to matrigels. By immunofluorescent staining, an unique spatial distribution of NRVMs and fibroblasts was identified. NRVMs formed the central core of engineered tissues, encapsulated by fibroblasts, which was similar to a native SAN. The application of a sympathomimetic drug (epinephrine) doubled the beating rate of reprogrammed engineered tissue (P=0.02, n=6-8). Conclusions: A pilot model of engineered SAN was established by TBX18-reprogrammed cardiomyocytes. The supportive cells such as fibroblasts played an important role in tissue engineering of SAN.

scholarly journals Unique Ca2+-Cycling Protein Abundance and Regulation Sustains Local Ca2+ Releases and Spontaneous Firing of Rabbit Sinoatrial Node Cells

2018 ◽  
Vol 19 (8) ◽  
pp. 2173 ◽  
Author(s):  
Tatiana Vinogradova ◽  
Syevda Tagirova (Sirenko) ◽  
Edward Lakatta
Keyword(s):  
Sinoatrial Node ◽  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Cell Types ◽  
Protein Abundance ◽  
Gradual Change ◽  
Spontaneous Firing ◽  
Diastolic Depolarization ◽  
Sinoatrial Node Cells ◽  
Rabbit Sinoatrial Node

Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) and caused by gradual change of the membrane potential called diastolic depolarization (DD). Submembrane local Ca2+ releases (LCR) from sarcoplasmic reticulum (SR) occur during late DD and activate an inward Na+/Ca2+ exchange current, which accelerates the DD rate leading to earlier occurrence of an action potential. A comparison of intrinsic SR Ca2+ cycling revealed that, at similar physiological Ca2+ concentrations, LCRs are large and rhythmic in permeabilized SANC, but small and random in permeabilized ventricular myocytes (VM). Permeabilized SANC spontaneously released more Ca2+ from SR than VM, despite comparable SR Ca2+ content in both cell types. In this review we discuss specific patterns of expression and distribution of SR Ca2+ cycling proteins (SR Ca2+ ATPase (SERCA2), phospholamban (PLB) and ryanodine receptors (RyR)) in SANC and ventricular myocytes. We link ability of SANC to generate larger and rhythmic LCRs with increased abundance of SERCA2, reduced abundance of the SERCA inhibitor PLB. In addition, an increase in intracellular [Ca2+] increases phosphorylation of both PLB and RyR exclusively in SANC. The differences in SR Ca2+ cycling protein expression between SANC and VM provide insights into diverse regulation of intrinsic SR Ca2+ cycling that drives automaticity of SANC.

P2565Decreased cardiac pacemaking and attenuated beta-adrenergic response in tric-a knock-out mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Toyama ◽  
M Yonekura ◽  
H Tomita ◽  
M Murakami
Keyword(s):  
Heart Rate ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Sinus Node ◽  
Ryanodine Receptors ◽  
Contractile Force ◽  
Knock Out ◽  
Isolated Hearts ◽  
Sinus Rate ◽  
Cardiac Pacemaking

Abstract Background Trimeric intracellular cation (TRIC) channels are expressed on the surface of the sarcoplasmic reticulum and compensate for calcium release from ryanodine receptors. Tric-a knock-out (KO) mice showed diminished calcium release from ryanodine receptors in vascular smooth muscle cells. The cardiac pacemaker is controlled by the surface membrane and intracellular calcium clocks. In spontaneously firing sinus node action potentials, the membrane and calcium clocks work together via numerous interactions modulated by membrane voltage, intracellular calcium release, and protein phosphorylation. Intracellular calcium changes modulate cardiac pacemaking in the sinus node, but the physiological importance of TRIC channels in cardiac rhythm formation is still obscure. Purpose In this study, we aimed to clarify the importance of TRIC channels on cardiac pacemaking using Tric-a KO mice. Methods The expression level of mRNA and proteins in the sinus node was examined by RT-PCR and immunoblotting. Systolic blood pressure was measured with tail-cuff method. Heart rate was measured by ECG, and heart rate variability was examined. The atrial contractile force from isolated hearts was measured with a force transducer. Cardiac action potential and spontaneous sinus rate from isolated hearts were measured with a microelectrode. Isoproterenol was used for sympathetic nerve manipulation. Results Tric-a KO heart showed increased adrenergic β1-receptor expression in immunoblotting. Although there was no significant difference in basal systolic blood pressure between Tric-a KO and wild type (WT) mice, basal heart rate in Tric-a KO mice was significantly lower than that in WT mice (660±10 and 698±10 bpm, n=15 and 19, Tric-a KO mice and WT mice, respectively, p=0.017). Tric-a KO mice showed limited heart rate changes to isoproterenol (24±6 and 99±15 bpm, n=9 and 10, Tric-a KO mice and WT mice, respectively, p<0.001). In the action potential recordings, Tric-a KO atria showed only limited sinus rate changes to isoproterenol (35±9 and 71±10 bpm, n=8 and 6, Tric-a KO mice and WT mice, respectively, p=0.038). WT mice and Tric-a KO mice atrial contractile force showed dose-dependent changes in response to isoproterenol (10–100 nM), but Tric-a KO mice atria showed limited contractile force changes to isoproterenol (116 and 169%, n=7 and 6, Tric-a KO mice and WT mice, respectively, p<0.01). In heart rate variability, Tric-a KO mice showed unstable RR intervals and longer standard deviation of RR intervals than WT mice. Conclusion Tric-a KO mice showed decreased cardiac pacemaking in the sinus node and attenuated responses to beta-adrenergic stimulus, which indicates the involvement of TRIC channels in cardiac rhythm formation and sympathetic nerve regulation.

Selected Contribution: Axial stretch increases spontaneous pacemaker activity in rabbit isolated sinoatrial node cells

2000 ◽  
Vol 89 (5) ◽  
pp. 2099-2104 ◽  
Author(s):  
Patricia J. Cooper ◽  
Ming Lei ◽  
Long-Xian Cheng ◽  
Peter Kohl
Keyword(s):  
Voltage Clamp ◽  
Sinoatrial Node ◽  
Reversal Potential ◽  
Pacemaker Activity ◽  
Chronotropic Response ◽  
Beating Rate ◽  
Sinoatrial Node Cells ◽  
Patch Configuration ◽  
Longitudinal Stretch ◽  
Reported Data

Isolated, spontaneously beating rabbit sinoatrial node cells were subjected to longitudinal stretch, using carbon fibers attached to both ends of the cell. Their electrical behavior was studied simultaneously in current-clamp or voltage-clamp mode using the perforated patch configuration. Moderate stretch (∼7%) caused an increase in spontaneous beating rate (by ∼5%) and a reduction in maximum diastolic and systolic potentials (by ∼2.5%), as seen in multicellular preparations. Mathematical modeling of the stretch intervention showed the experimental results to be compatible with stretch activation of cation nonselective ion channels, similar to those found in other cardiac cell populations. Voltage-clamp experiments validated the presence of a stretch-induced current component with a reversal potential near −11 mV. These data confirm, for the first time, that the positive chronotropic response of the heart to stretch is, at least in part, encoded on the level of individual sinoatrial node pacemaker cells; all reported data are in agreement with a major contribution of stretch-activated cation nonselective channels to this response.

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