Abstract
Cardiac-specific Na$^+$-Ca$^2+$ 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 Ca$^2+$, and action potentials (APs) in whole cell
patch-clamped myocytes from wild-type (WT) and NCX knockout mice.
There was no difference in resting Ca$^2+$ or sarcoplasmic reticular
Ca$^2+$ load between KO and WT. During prolonged caffeine exposure,
the decrease of the Ca$^2+$ transient was drastically slowed
in KO versus WT myocytes, indicating that no alternative Ca$^2+$-extrusion
mechanism is upregulated to compensate for the absence of NCX. Peak
L-type Ca$^2+$ current (ICa) was reduced by 62\% in KO myocytes
compared with WT. Nevertheless, the corresponding Ca$^2+$ 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 Ca$^2+$ influx via ICa by 59\% compared with WT
AP waveform clamps. Again, the corresponding Ca$^2+$ transients
remained similar. Our findings indicate that NCX KO myocytes limit
Ca$^2+$ 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.
- 16293789
- action
- animals,
- ca,
- cardiac,
- contraction,
- exchanger,
- extramural,
- gov't,
- knockout,
- lcium,
- mice,
- myocardial
- myocytes,
- n.i.h.,
- non-u.s.
- potentials,
- research
- sarcolemma,
- sodium-calcium
- support,
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