Synergistic interactions between Ca$^2+$ entries through L-type
Ca$^2+$ channels and Na$^+$-Ca$^2+$ exchanger in normal
and failing rat heart.
J. Physiol. 567 (Pt 2): 493--504 (September 2005)
Abstract
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.
Description
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Links and resources
- DOI:
- 10.1113/jphysiol.2005.091280
- URL:
- http://dx.doi.org/10.1113/jphysiol.2005.091280
- BibTeX key:
- Karp_2005_493
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