File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Rhythmic beating of stem cell-derived cardiac cells requires dynamic coupling of electrophysiology and Ca cycling

TitleRhythmic beating of stem cell-derived cardiac cells requires dynamic coupling of electrophysiology and Ca cycling
Authors
Issue Date2011
Citation
Journal of Molecular and Cellular Cardiology, 2011, v. 50 n. 1, p. 66-76 How to Cite?
AbstractThere is an intense interest in differentiating embryonic stem cells to engineer biological pacemakers as an alternative to electronic pacemakers for patients with cardiac pacemaker function deficiency. Embryonic stem cell-derived cardiocytes (ESCs), however, often exhibit dysrhythmic excitations. Using Ca 2+ imaging and patch-clamp techniques, we studied requirements for generation of spontaneous rhythmic action potentials (APs) in late-stage mouse ESCs. Sarcoplasmic reticulum (SR) of ESCs generates spontaneous, rhythmic, wavelet-like Local Ca 2+ Releases (LCRs) (inhibited by ryanodine, tetracaine, or thapsigargin). L-type Ca 2+current (I CaL) induces a global Ca 2+ release (CICR), depleting the Ca 2+ content SR which resets the phases of LCR oscillators. Following a delay, SR then generates a highly synchronized spontaneous Ca 2+release of multiple LCRs throughout the cell. The LCRs generate an inward Na +/Ca 2+exchanger (NCX) current (absent in Na +-free solution) that ignites the next AP. Interfering with SR Ca 2+ cycling (ryanodine, caffeine, thapsigargin, cyclopiazonic acid, BAPTA-AM), NCX (Na +-free solution), or I CaL (nifedipine) results in dysrhythmic excitations or cessation of automaticity. Inhibition of cAMP/PKA signaling by a specific PKA inhibitor, PKI, decreases SR Ca 2+ loading, substantially reducing both spontaneous LCRs (number, size, and amplitude) and rhythmic AP firing. In contrast, enhancing PKA signaling by cAMP increases the LCRs (number, size, duration) and converts irregularly beating ESCs to rhythmic "pacemaker-like" cells. SR Ca 2+ loading and LCR activity could be also increased with a selective activation of SR Ca 2+ pumping by a phospholamban antibody. We conclude that SR Ca 2+ loading and spontaneous rhythmic LCRs are driven by inherent cAMP/PKA activity. I CaL synchronizes multiple LCR oscillators resulting in strong, partially synchronized diastolic Ca 2+ release and NCX current. Rhythmic ESC automaticity can be achieved by boosting "coupling" factors, such as cAMP/PKA signaling, that enhance interactions between SR and sarcolemma. © 2010.
Persistent Identifierhttp://hdl.handle.net/10722/195136
ISSN
2015 Impact Factor: 4.874
2015 SCImago Journal Rankings: 2.522
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZahanich, I-
dc.contributor.authorSirenko, SG-
dc.contributor.authorMaltseva, LA-
dc.contributor.authorTarasova, YS-
dc.contributor.authorSpurgeon, HA-
dc.contributor.authorBoheler, KR-
dc.contributor.authorStern, MD-
dc.contributor.authorLakatta, EG-
dc.contributor.authorMaltsev, VA-
dc.date.accessioned2014-02-25T01:40:13Z-
dc.date.available2014-02-25T01:40:13Z-
dc.date.issued2011-
dc.identifier.citationJournal of Molecular and Cellular Cardiology, 2011, v. 50 n. 1, p. 66-76-
dc.identifier.issn0022-2828-
dc.identifier.urihttp://hdl.handle.net/10722/195136-
dc.description.abstractThere is an intense interest in differentiating embryonic stem cells to engineer biological pacemakers as an alternative to electronic pacemakers for patients with cardiac pacemaker function deficiency. Embryonic stem cell-derived cardiocytes (ESCs), however, often exhibit dysrhythmic excitations. Using Ca 2+ imaging and patch-clamp techniques, we studied requirements for generation of spontaneous rhythmic action potentials (APs) in late-stage mouse ESCs. Sarcoplasmic reticulum (SR) of ESCs generates spontaneous, rhythmic, wavelet-like Local Ca 2+ Releases (LCRs) (inhibited by ryanodine, tetracaine, or thapsigargin). L-type Ca 2+current (I CaL) induces a global Ca 2+ release (CICR), depleting the Ca 2+ content SR which resets the phases of LCR oscillators. Following a delay, SR then generates a highly synchronized spontaneous Ca 2+release of multiple LCRs throughout the cell. The LCRs generate an inward Na +/Ca 2+exchanger (NCX) current (absent in Na +-free solution) that ignites the next AP. Interfering with SR Ca 2+ cycling (ryanodine, caffeine, thapsigargin, cyclopiazonic acid, BAPTA-AM), NCX (Na +-free solution), or I CaL (nifedipine) results in dysrhythmic excitations or cessation of automaticity. Inhibition of cAMP/PKA signaling by a specific PKA inhibitor, PKI, decreases SR Ca 2+ loading, substantially reducing both spontaneous LCRs (number, size, and amplitude) and rhythmic AP firing. In contrast, enhancing PKA signaling by cAMP increases the LCRs (number, size, duration) and converts irregularly beating ESCs to rhythmic "pacemaker-like" cells. SR Ca 2+ loading and LCR activity could be also increased with a selective activation of SR Ca 2+ pumping by a phospholamban antibody. We conclude that SR Ca 2+ loading and spontaneous rhythmic LCRs are driven by inherent cAMP/PKA activity. I CaL synchronizes multiple LCR oscillators resulting in strong, partially synchronized diastolic Ca 2+ release and NCX current. Rhythmic ESC automaticity can be achieved by boosting "coupling" factors, such as cAMP/PKA signaling, that enhance interactions between SR and sarcolemma. © 2010.-
dc.languageeng-
dc.relation.ispartofJournal of Molecular and Cellular Cardiology-
dc.titleRhythmic beating of stem cell-derived cardiac cells requires dynamic coupling of electrophysiology and Ca cycling-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.yjmcc.2010.09.018-
dc.identifier.pmid20920509-
dc.identifier.scopuseid_2-s2.0-78650835205-
dc.identifier.volume50-
dc.identifier.issue1-
dc.identifier.spage66-
dc.identifier.epage76-
dc.identifier.isiWOS:000286502800012-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats