Excitation-contraction coupling in Na+-Ca2+ exchanger knockout mice: reduced transsarcolemmal Ca2+ flux.
Cardiac-specific Na+-Ca2+ exchanger (NCX) knockout (KO) mice surprisingly survive into adulthood without compensatory changes in protein expression levels. To determine how cardiac function is maintained in the absence of NCX, we investigated membrane currents, intracellular Ca2+, and action potentials (APs) in whole cell patch-clamped myocytes from wild-type (WT) and NCX knockout mice. There was no difference in resting Ca2+ or sarcoplasmic reticular Ca2+ load between KO and WT. During prolonged caffeine exposure, the decrease of the Ca2+ transient was drastically slowed in KO versus WT myocytes, indicating that no alternative Ca2+-extrusion mechanism is upregulated to compensate for the absence of NCX. Peak L-type Ca2+ current (ICa) was reduced by 62% in KO myocytes compared with WT. Nevertheless, the corresponding Ca2+ transients were similar, implying an increase in the gain of excitation-contraction coupling in KO cells. APs recorded from KO cells repolarized more rapidly than in WT. In WT myocytes, applying a KO AP waveform voltage clamp reduced Ca2+ influx via ICa by 59% compared with WT AP waveform clamps. Again, the corresponding Ca2+ transients remained similar. Our findings indicate that NCX KO myocytes limit Ca2+ influx to &20% of that in WT by reducing ICa and by abbreviating the AP. Contractility is maintained by an increase in the gain of excitation-contraction coupling resulting from both a more rapid repolarization of the AP and an as yet unidentified AP-independent mechanism.
Pott
Christian
C
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1760, USA.
Philipson
Kenneth D
KD
Goldhaber
Joshua I
JI
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology*; D012508:Sarcolemma / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000502:physiology*
D019831:Sodium-Calcium Exchanger; D002118:Calcium