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Cell Calcium. 2018 Sep;74:168-179. doi: 10.1016/j.ceca.2018.07.002. Epub 2018 Jul 10.

Heterogeneity of calcium clock functions in dormant, dysrhythmically and rhythmically firing single pacemaker cells isolated from SA node.

Author information

1
Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Biomedical Research Center, 251 Bayview Blvd. Suite 100, Baltimore, MD 21224-6825, USA.
2
Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Biomedical Research Center, 251 Bayview Blvd. Suite 100, Baltimore, MD 21224-6825, USA; Department of Cardiovascular Electrophysiology, The Johns Hopkins Hospital, 1800 Orleans St, Baltimore, MD 21287, USA; Institute of Cardiovascular Sciences, University of Manchester, 46 Grafton St, Manchester M13 9NT, UK.
3
Farncombe Institute, McMaster University, Hamilton, ON, Canada.
4
Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Biomedical Research Center, 251 Bayview Blvd. Suite 100, Baltimore, MD 21224-6825, USA. Electronic address: maltsevvi@mail.nih.gov.

Abstract

Current understanding of how cardiac pacemaker cells operate is based mainly on studies in isolated single sinoatrial node cells (SANC), specifically those that rhythmically fire action potentials similar to the in vivo behavior of the intact sinoatrial node. However, only a small fraction of SANC exhibit rhythmic firing after isolation. Other SANC behaviors have not been studied. Here, for the first time, we studied all single cells isolated from the sinoatrial node of the guinea pig, including traditionally studied rhythmically firing cells ('rhythmic SANC'), dysrhythmically firing cells ('dysrhythmic SANC') and cells without any apparent spontaneous firing activity ('dormant SANC'). Action potential-induced cytosolic Ca2+ transients and spontaneous local Ca2+ releases (LCRs) were measured with a 2D camera. LCRs were present not only in rhythmically firing SANC, but also in dormant and dysrhythmic SANC. While rhythmic SANC were characterized by large LCRs synchronized in space and time towards late diastole, dysrhythmic and dormant SANC exhibited smaller LCRs that appeared stochastically and were widely distributed in time. β-adrenergic receptor (βAR) stimulation increased LCR size and synchronized LCR occurrences in all dysrhythmic and a third of dormant cells (25 of 75 cells tested). In response to βAR stimulation, these dormant SANC developed automaticity, and LCRs became coupled to spontaneous action potential-induced cytosolic Ca2+ transients. Conversely, dormant SANC that did not develop automaticity showed no significant change in average LCR characteristics. The majority of dysrhythmic cells became rhythmic in response to βAR stimulation, with the rate of action potential-induced cytosolic Ca2+ transients substantially increasing. In summary, isolated SANC can be broadly categorized into three major populations: dormant, dysrhythmic, and rhythmic. We interpret our results based on simulations of a numerical model of SANC operating as a coupled-clock system. On this basis, the two previously unstudied dysrhythmic and dormant cell populations have intrinsically partially or completely uncoupled clocks. Such cells can be recruited to fire rhythmically in response to βAR stimulation via increased rhythmic LCR activity and ameliorated coupling between the Ca2+ and membrane clocks.

KEYWORDS:

Local calcium release; Pacemaker; Ryanodine receptor; Sarcoplasmic reticulum; Sinoatrial node; β Adrenergic receptor

PMID:
30092494
PMCID:
PMC6402562
DOI:
10.1016/j.ceca.2018.07.002
[Indexed for MEDLINE]
Free PMC Article

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