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

79 Citations (Scopus)

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

Fingerprint

Ryanodine Receptor Calcium Release Channel
Cardiac Myocytes
Muscle Cells
Embryonic Stem Cells
Heart Rate
Ryanodine
Sinoatrial Node
Calcium Signaling
Human Herpesvirus 1
Action Potentials
Myocardium
Membranes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development. / Yang, Huang Tian; Tweedie, David; Wang, Su; Guia, Antonio; Vinogradova, Tatiana; Bogdanov, Konstantin; Allen, Paul D.; Stern, Michael D.; Lakatta, Edward G.; Boheler, Kenneth R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 14, 09.07.2002, p. 9225-9230.

Research output: Contribution to journalArticle

Yang, HT, Tweedie, D, Wang, S, Guia, A, Vinogradova, T, Bogdanov, K, Allen, PD, Stern, MD, Lakatta, EG & Boheler, KR 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, vol. 99, no. 14, pp. 9225-9230. https://doi.org/10.1073/pnas.142651999
Yang, Huang Tian ; Tweedie, David ; Wang, Su ; Guia, Antonio ; Vinogradova, Tatiana ; Bogdanov, Konstantin ; Allen, Paul D. ; Stern, Michael D. ; Lakatta, Edward G. ; Boheler, Kenneth R. / The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 14. pp. 9225-9230.
@article{7c7b7f584d694763a35494b6a21674a2,
title = "The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development",
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.",
author = "Yang, {Huang Tian} and David Tweedie and Su Wang and Antonio Guia and Tatiana Vinogradova and Konstantin Bogdanov and Allen, {Paul D.} and Stern, {Michael D.} and Lakatta, {Edward G.} and Boheler, {Kenneth R.}",
year = "2002",
month = "7",
day = "9",
doi = "10.1073/pnas.142651999",
language = "English (US)",
volume = "99",
pages = "9225--9230",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "14",

}

TY - JOUR

T1 - The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development

AU - Yang, Huang Tian

AU - Tweedie, David

AU - Wang, Su

AU - Guia, Antonio

AU - Vinogradova, Tatiana

AU - Bogdanov, Konstantin

AU - Allen, Paul D.

AU - Stern, Michael D.

AU - Lakatta, Edward G.

AU - Boheler, Kenneth R.

PY - 2002/7/9

Y1 - 2002/7/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037047145&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037047145&partnerID=8YFLogxK

U2 - 10.1073/pnas.142651999

DO - 10.1073/pnas.142651999

M3 - Article

C2 - 12089338

AN - SCOPUS:0037047145

VL - 99

SP - 9225

EP - 9230

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 14

ER -