HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/3/C732    most recent 00025.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Guo, A. Articles by Yang, H.-T. PubMed PubMed Citation Articles by Guo, A. Articles by Yang, H.-T.

MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Ca²⁺ removal mechanisms in mouse embryonic stem cell-derived cardiomyocytes

¹Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine; ²Shanghai Stem Cell Institute, Shanghai Jiao Tong University School of Medicine; and ³Shanghai Key Laboratory of Vascular Biology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Submitted 15 January 2009 ; accepted in final form 13 July 2009

In mammalian adult cardiomyocytes, sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA) plays a major role in controlling the decline of cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) in comparison with sarcolemmal Na⁺/Ca²⁺ exchanger (NCX). However, the functional importance of SERCA and NCX in cytosolic Ca²⁺ removal during early cardiomyogenesis is still debated. In this study, the functional contributions of Ca²⁺ transporters to [Ca²⁺]_i decline in mouse embryonic stem cell-derived cardiomyocytes (mESCMs), a suitable model for investigation of early cardiogenesis, at various differentiation stages were investigated. We estimated that even at early differentiation stages of mESCMs, SERCA was responsible for 76% of total Ca²⁺ removal, while NCX was responsible for 21%. The contributions of SERCA and NCX to cytosolic Ca²⁺ clearance were increased to 88% and decreased to 10%, respectively, at the late differentiation stage. Dynamical analysis of the transient decay phases in normal and Na⁺-free solutions suggests that the contribution of NCX to [Ca²⁺]_i decline is more apparent in the terminal slow decay phase than that in the initial fast phase. When SR function was suppressed in type 2 ryanodine receptor-null mESCMs or with ryanodine receptor and SERCA inhibitors (ryanodine and thapsigargin), NCX acted as the main pathway for [Ca²⁺]_i decline. We conclude that the rapid [Ca²⁺]_i decline is mainly achieved by the SR uptake even at the early differentiation stage of mESCMs, while NCX acts as the main Ca²⁺ remover when SR function is suppressed. These findings suggest a critical role of SR in the regulation of [Ca²⁺]_i homeostasis even in differentiating cardiomyocytes.

sarcoplasmic reticulum; calcium transporters; sarcoplasmic reticulum Ca²⁺-ATPase; sodium/calcium exchanger