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This Article Full Text Full Text (PDF) All Versions of this Article: 567/2/493    most recent jphysiol.2005.091280v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Viatchenko-Karpinski, S. Articles by Györke, S. Search for Related Content PubMed PubMed Citation Articles by Viatchenko-Karpinski, S. Articles by Györke, S.

¹ Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University Medical Center, 473 West 12th Avenue, Columbus, OH 43210-1252, USA
² Division of Cardiology, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, USA
³ Department of Physiology, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, USA

We used confocal Ca²⁺ imaging and the patch-clamp technique to investigate the interplay between Ca²⁺ entries through L-type Ca²⁺ channels (LCCs) and reverse-mode Na⁺–Ca²⁺ exchange (NCX) in activating Ca²⁺-induced Ca²⁺ release (CICR) from the sarcoplasmic reticulum (SR) in cardiac myocytes from normal and failing rat hearts. In normal myocytes exposed to N(6),2'-O-dibutyryl adenosine-3',5'-cyclic monophosphate (db-cAMP, membrane-permeable form of cAMP), the bell-shaped voltage dependence of cytosolic Ca²⁺ transients was dramatically broadened due to activation of SR Ca²⁺ release at high membrane potentials (30–120 mV). This broadening of Ca²⁺-transient voltage dependence could be prevented by KB-R7943, an inhibitor of the reverse-mode NCX. Trans-sarcolemmal Ca²⁺ entries were measured fluorometrically in myocytes during depolarizing steps to high membrane potentials. The total Ca²⁺ entry (F_Tot) was separated into two Ca²⁺ entry components, LCC-mediated (F_LCC) and NCX-mediated (F_NCX), by exposing the cells to the specific inhibitors of LCCs and reverse-mode NCX, nifedipine and KB-R7943, respectively. In the absence of protein kinase A (PKA) stimulation the amplitude of the Ca²⁺-inflow signal (F_Tot) corresponded to the arithmetic sum of the amplitudes of the KB-R7943- and nifedipine-resistant components (F_Tot=F_LCC+F_NCX). PKA activation resulted in significant increases in F_Tot and F_LCC. Paradoxically, F_Tot became threefold larger than the sum of the F_NCX and F_LCC components. In myocytes from failing hearts, stimulation of PKA failed to induce a shift in Ca²⁺ release voltage dependence toward more positive membrane potentials. Although the total and NCX-mediated Ca²⁺ entries were increased again, F_Tot did not significantly exceed the sum of F_LCC and F_NCX. We conclude that the LCC and NCX Ca²⁺-entry pathways interact synergistically to trigger SR Ca²⁺ release on depolarization to positive membrane potentials in PKA-stimulated cardiac muscle. In heart failure, this new form of Ca²⁺ release is diminished and may potentially account for the compromised contractile performance and reduced functional reserve in failing hearts.

(Received 24 May 2005; accepted after revision 23 June 2005; first published online 23 June 2005)
Corresponding author S. Györke: Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, Ohio State University Medical Center, 473 West 12th Avenue, Columbus, OH 43210-1252, USA. Email: gyorke-1{at}medctr.osu.edu

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