Аннотация
Cardiac sarcolemmal Na$^+$--Ca$^2+$ exchange is a central
component of Ca$^2+$ signaling essential for Ca$^2+$ extrusion
and contributing to a variable degree to the development of the systolic
Ca$^2+$ transient. Reports on differential gene expression of
Na$^+$--Ca$^2+$ exchange in cardiac disease and the regulation
of its thermodynamic equilibrium depending on intracellular gradients
of ion concentrations between subcellular compartments have recently
put a new complexion on Na$^+$--Ca$^2+$ exchange and its
implications for excitation-contraction (E-C) coupling. Heart failure
models and genetic approaches to regulate expression of the Na$^+$--Ca$^2+$
exchanger have improved our knowledge of exchanger function. Modest
overexpression of the Na$^+$--Ca$^2+$ exchanger in heterozygous
transgenic mice had minimal effects on E-C coupling and cardiac function.
However, higher levels of Na$^+$--Ca$^2+$ exchange expression
in homozygotes led to pathological hypertrophy and failure with an
increased interaction between the L-type Ca$^2+$ current and
Na$^+$--Ca$^2+$ exchange and reduced E-C coupling gain. These
results suggested that the Na$^+$--Ca$^2+$ exchanger is capable
of modulating sarcoplasmic Ca$^2+$ handling and at high expression
levels may interact with the gating kinetics of the L-type Ca$^2+$
current by means of regulating subsarcolemmal Ca$^2+$ levels.
Despite being a central component in the regulation of cardiac E-C
coupling, a newly generated mouse model with cardiac-specific conditional
knock-out of the Na$^+$--Ca$^2+$ exchanger is viable with
unchanged Ca$^2+$ dynamics in adult ventricular myocytes. Cardiac
myocytes adapt well to knock-out of the exchanger, apparently by
reducing transsarcolemmal fluxes of Ca$^2+$ and increasing E-C
coupling gain possibly mediated by changes in submembrane Ca$^2+$
levels. For E-C coupling in the murine model, which relies primarily
on sarcoplasmic Ca$^2+$ regulation, this led to the suggestion
that the role of Na$^+$--Ca$^2+$ exchange should be thought
of as a Ca$^2+$ buffering function and not as a major Ca$^2+$
transporter in competition with the sarcoplasmic reticulum.
- 15935336
- action
- animals,
- ca,
- calcium
- calcium,
- cardiac,
- cardiomegaly,
- contraction,
- disease,
- electrophysiology,
- energy
- exchanger,
- extramural,
- genetic
- gov't,
- homozygote,
- humans,
- hypertrophy,
- injury,
- isoproterenol,
- knockout,
- lcium,
- left
- metabolism,
- mice,
- myocardial
- myocardium,
- myocytes,
- n.i.h.,
- non-u.s.
- p.h.s.,
- phenotype,
- potentials,
- predisposition
- reperfusion
- research
- reticulum,
- sarcolemma,
- sarcoplasmic
- signaling,
- sodium,
- sodium-calcium
- support,
- to
- transgenic,
- u.s.
- ventricular,
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