Synergistic interactions between Ca$^2+$ entries through L-type Ca$^2+$ channels and Na$^+$-Ca$^2+$ exchanger in normal and failing rat heart.

S. Viatchenko-Karpinski, D. Terentyev, L. Jenkins, L. Lutherer, and S. Gy�rke. J. Physiol. 567 (Pt 2): 493--504 (September 2005)


We used confocal Ca$^2+$ imaging and the patch-clamp technique to investigate the interplay between Ca$^2+$ entries through L-type Ca$^2+$ channels (LCCs) and reverse-mode Na$^+$-Ca$^2+$ exchange (NCX) in activating Ca$^2+$-induced Ca$^2+$ 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 Ca$^2+$ transients was dramatically broadened due to activation of SR Ca$^2+$ release at high membrane potentials (30-120 mV). This broadening of Ca$^2+$-transient voltage dependence could be prevented by KB-R7943, an inhibitor of the reverse-mode NCX. Trans-sarcolemmal Ca$^2+$ entries were measured fluorometrically in myocytes during depolarizing steps to high membrane potentials. The total Ca$^2+$ entry (deltaF(Tot)) was separated into two Ca$^2+$ entry components, LCC-mediated (deltaF(LCC)) and NCX-mediated (deltaF(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 Ca$^2+$-inflow signal (deltaF(Tot)) corresponded to the arithmetic sum of the amplitudes of the KB-R7943- and nifedipine-resistant components (deltaF(Tot)=deltaF(LCC)+deltaF(NCX)). PKA activation resulted in significant increases in deltaF(Tot) and deltaF(LCC). Paradoxically, deltaF(Tot) became approximately threefold larger than the sum of the deltaF(NCX) and deltaF(LCC) components. In myocytes from failing hearts, stimulation of PKA failed to induce a shift in Ca$^2+$ release voltage dependence toward more positive membrane potentials. Although the total and NCX-mediated Ca$^2+$ entries were increased again, deltaF(Tot) did not significantly exceed the sum of deltaF(LCC) and deltaF(NCX). We conclude that the LCC and NCX Ca$^2+$-entry pathways interact synergistically to trigger SR Ca$^2+$ release on depolarization to positive membrane potentials in PKA-stimulated cardiac muscle. In heart failure, this new form of Ca$^2+$ release is diminished and may potentially account for the compromised contractile performance and reduced functional reserve in failing hearts.


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