Abstract
The excitation-contraction coupling cycle in cardiac muscle is initiated
by an influx of Ca$^2+$ through voltage-dependent Ca$^2+$
channels. Ca$^2+$ influx induces a release of Ca$^2+$ from
the sarcoplasmic reticulum and myocyte contraction. To maintain Ca$^2+$
homeostasis, Ca$^2+$ entry is balanced by efflux mediated by
the sarcolemmal Na$^+$-Ca$^2+$ exchanger. In the absence
of Na$^+$-Ca$^2+$ exchange, it would be expected that cardiac
myocytes would overload with Ca$^2+$. Using Cre/loxP technology,
we generated mice with a cardiac-specific knockout of the Na$^+$-Ca$^2+$
exchanger, NCX1. The exchanger is completely ablated in 80\% to 90\%
of the cardiomyocytes as determined by immunoblot, immunofluorescence,
and exchange function. Surprisingly, the NCX1 knockout mice live
to adulthood with only modestly reduced cardiac function as assessed
by echocardiography. At 7.5 weeks of age, measures of contractility
are decreased by 20\% to 30\%. We detect no adaptation of the myocardium
to the absence of the Na$^+$-Ca$^2+$ exchanger as measured
by both immunoblots and microarray analysis. Ca$^2+$ transients
of isolated myocytes from knockout mice display normal magnitudes
and relaxation kinetics and normal responses to isoproterenol. Under
voltage clamp conditions, the current through L-type Ca$^2+$
channels is reduced by 50\%, although the number of channels is unchanged.
An abbreviated action potential may further reduce Ca$^2+$ influx.
Rather than upregulate other Ca$^2+$ efflux mechanisms, the myocardium
appears to functionally adapt to the absence of the Na$^+$-Ca$^2+$
exchanger by limiting Ca$^2+$ influx. The magnitude of Ca$^2+$
transients appears to be maintained by an increased gain of sarcoplasmic
reticular Ca$^2+$ release. The myocardium of the NCX1 knockout
mice undergoes a remarkable adaptation to maintain near normal cardiac
function.
- 15375019
- action
- adaptation,
- animals,
- calcium
- cardiac,
- contraction,
- deletion,
- echocardiography,
- exchanger,
- exons,
- female,
- fetal
- gene
- gov't,
- heart,
- integrases,
- knockout,
- male,
- mice,
- models,
- molecular,
- myocardial
- myocardium,
- myocytes,
- non-u.s.
- p.h.s.,
- patch-clamp
- physiological,
- potentials,
- proteins,
- research
- reticulum,
- sarcoplasmic
- sequence
- signaling,
- sodium-calcium
- support,
- targeting,
- techniques,
- u.s.
- viral
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