Article
Sarcoplasmic reticulum Ca2+ release is not a dominating factor in sinoatrial node pacemaker activity.
Department of Humoral Regulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
Circulation Research (impact factor:
9.49).
03/2003;
92(3):e41-4.
pp.e41-4
Source: PubMed
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Citations (0)
- Cited In (3)
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Article: Ankyrin-based targeting pathway regulates human sinoatrial node automaticity.
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ABSTRACT: Cellular defects in ankyrin-based ion channels and transporter targeting pathways have previously been linked with abnormal vertebrate physiology and human disease. In a recent study, our group linked dysfunction in cardiac ankyrin-B function with human sinus node disease. Ankyrin-B deficient mice displayed bradycardia and heart rate variability similar to individuals harboring an ANK2 variant. Isolated sinoatrial node (SAN) cells from ankyrin-B-deficient animals displayed abnormal membrane expression of Na+/Ca2+ exchanger (NCX1), Na+/K+ ATPase (NKA), IP3 receptor (IP3R) and, surprisingly, Ca(V)1.3. Loss of ankyrin-B promoted slow and irregular Ca2+ release, as well as afterdepolarizations in isolated SAN cardiomyocytes. Our findings suggest that ankyrin-B serves as a critical focal point for channels and transporters important for sarcoplasmic reticulum (SR) calcium homeostasis as well as membrane depolarization in SAN cells. The severity and penetrance of human ANK2 sinus node dysfunction likely reflects the essential role of ankyrin-B for orchestrating membrane function of multiple SAN ion channel and transporters within a single functional pathway. Therefore, ankyrin-based pathways may serve as ideal therapeutic targets in SAN cardiomyocytes where a "multi-hit" approach is necessary to impact a complex process such as SAN cell automaticity. In summary, our new findings define a novel genetic basis for human SND and expand our understanding of the critical role that ankyrin-based targeting pathways play in excitable cell physiology.Channels (Austin, Tex.) 12/2008; 2(6):404-6. · 1.91 Impact Factor -
Article: Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells.
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ABSTRACT: We investigated the contribution of the intracellular calcium (Ca (i) (2+) ) transient to acetylcholine (ACh)-mediated reduction of pacemaker frequency and cAMP content in rabbit sinoatrial nodal (SAN) cells. Action potentials (whole cell perforated patch clamp) and Ca (i) (2+) transients (Indo-1 fluorescence) were recorded from single isolated rabbit SAN cells, whereas intracellular cAMP content was measured in SAN cell suspensions using a cAMP assay (LANCE((R))). Our data show that the Ca (i) (2+) transient, like the hyperpolarization-activated "funny current" (I (f)) and the ACh-sensitive potassium current (I (K,ACh)), is an important determinant of ACh-mediated pacemaker slowing. When I (f) and I (K,ACh) were both inhibited, by cesium (2 mM) and tertiapin (100 nM), respectively, 1 micro M ACh was still able to reduce pacemaker frequency by 72%. In these I (f) and I (K,ACh)-inhibited SAN cells, good correlations were found between the ACh-mediated change in interbeat interval and the ACh-mediated change in Ca (i) (2+) transient decay (r (2) = 0.98) and slow diastolic Ca (i) (2+) rise (r (2) = 0.73). Inhibition of the Ca (i) (2+) transient by ryanodine (3 microM) or BAPTA-AM (5 microM) facilitated ACh-mediated pacemaker slowing. Furthermore, ACh depressed the Ca (i) (2+) transient and reduced the sarcoplasmic reticulum (SR) Ca(2+) content, all in a concentration-dependent fashion. At 1 microM ACh, the spontaneous activity and Ca (i) (2+) transient were abolished, but completely recovered when cAMP production was stimulated by forskolin (10 microM) and I (K,ACh) was inhibited by tertiapin (100 nM). Also, inhibition of the Ca (i) (2+) transient by ryanodine (3 microM) or BAPTA-AM (25 microM) exaggerated the ACh-mediated inhibition of cAMP content, indicating that Ca (i) (2+) affects cAMP production in SAN cells. In conclusion, muscarinic receptor stimulation inhibits the Ca (i) (2+) transient via a cAMP-dependent signaling pathway. Inhibition of the Ca (i) (2+) transient contributes to pacemaker slowing and inhibits Ca (i) (2+) -stimulated cAMP production. Thus, we provide functional evidence for the contribution of the Ca (i) (2+) transient to ACh-induced inhibition of pacemaker activity and cAMP content in rabbit SAN cells.Archiv für Kreislaufforschung 08/2009; 105(1):73-87. · 7.35 Impact Factor -
Article: The pacemaker current: from basics to the clinics.
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ABSTRACT: Activation of the pacemaker ("funny," I(f)) current during diastole is the main process underlying generation of the diastolic depolarization and spontaneous activity of cardiac pacemaker cells. I(f) modulation by autonomic transmitters is responsible for the chronotropic regulation of heart rate. Given its role in pacemaking, I(f) has been a major target of investigation aimed to exploit its rate-controlling function in a clinical perspective. In this short review, we describe some of the most recent clinically relevant applications of the concept of I(f)-based pacemaking.Journal of Cardiovascular Electrophysiology 04/2007; 18(3):342-7. · 3.06 Impact Factor
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Keywords
30 micromol/L blocks sarcoplasmic reticulum Ca2+ release
30 micromol/L ryanodine
beta-adrenergic stimulation
chronotropic effect
dominant role
dominating role
extracellular electrodes
full text
intact sinoatrial node
leading pacemaker site
lower concentration abolishes
Recent work
Ryanodine 30 micromol/L
ryanodine treatment
sarcoplasmic reticulum Ca2+ release
sinoatrial node
sinoatrial node cells
Spontaneous activity
spontaneous rate
substantial chronotropic effect