NDLI: Synergistic interactions between Ca2+ entries through L-type Ca2+ channels and Na+–Ca2+ exchanger in normal and failing rat heart

Content Provider	PubMed Central
Author	Serge, Viatchenko-karpinski Terentyev, Dmitry Jenkins, Leigh Ann Lutherer, Lorenz O. Sandor, Györke
Copyright Year	2005
Abstract	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 (ΔF Tot) was separated into two Ca2+ entry components, LCC-mediated (ΔF LCC) and NCX-mediated (ΔF 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 (ΔF Tot) corresponded to the arithmetic sum of the amplitudes of the KB-R7943- and nifedipine-resistant components (ΔF Tot=ΔF LCC+ΔF NCX). PKA activation resulted in significant increases in ΔF Tot and ΔF LCC. Paradoxically, ΔF Tot became ∼threefold larger than the sum of the ΔF NCX and ΔF 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, ΔF Tot did not significantly exceed the sum of ΔF LCC and ΔF 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.
Related Links	http://dx.doi.org/10.1113/jphysiol.2005.091280
Ending Page	504
Page Count	12
Starting Page	493
File Format	PDF
ISSN	00223751
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 2
Volume Number	567
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2005-09-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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