The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development

Huang Tian Yang, David Tweedie, Su Wang, Antonio Guia, Tatiana Vinogradova, Konstantin Bogdanov, Paul D. Allen, Michael D. Stern, Edward G. Lakatta, Kenneth R. Boheler

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

In adult myocardium, the heartbeat originates from the sequential activation of ionic currents in pacemaker cells of the sinoatrial node. Ca2+ release via the ryanodine receptor (RyR) modulates the rate at which these cells beat. In contrast, the mechanisms that regulate heart rate during early cardiac development are poorly understood. Embryonic stem (ES) cells can differentiate into spontaneously contracting myocytes whose beating rate increases with differentiation time. These cells thus offer an opportunity to determine the mechanisms that regulate heart rate during development. Here we show that the increase in heart rate with differentiation is markedly depressed in ES cell-derived cardiomyocytes with a functional knockout (KO) of the cardiac ryanodine receptor (RyR2). KO myocytes show a slowing of the rate of spontaneous diastolic depolarization and an absence of calcium sparks. The depressed rate of pacemaker potential can be mimicked in wild-type myocytes by ryanodine, and rescued in KO myocytes with herpes simplex virus (HSV)-1 amplicons containing full-length RyR2. We conclude that a functional RyR2 is crucial to the progressive increase in heart rate during differentiation of ES cell-derived cardiomyocytes, consistent with a mechanism that couples Ca2+ release via RyR before an action potential with activation of an inward current that accelerates membrane depolarization.

Original languageEnglish (US)
Pages (from-to)9225-9230
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number14
DOIs
StatePublished - Jul 9 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Yang, H. T., Tweedie, D., Wang, S., Guia, A., Vinogradova, T., Bogdanov, K., Allen, P. D., Stern, M. D., Lakatta, E. G., & Boheler, K. R. (2002). The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development. Proceedings of the National Academy of Sciences of the United States of America, 99(14), 9225-9230. https://doi.org/10.1073/pnas.142651999