Zusammenfassung
In cardiac muscle Ca$^2+$-induced Ca$^2+$ release (CICR) from
the sarcoplasmic reticulum (SR) is initiated by Ca$^2+$ influx
via L-type Ca$^2+$ channels. At present, the mechanisms underlying
termination of SR Ca$^2+$ release, which are required to ensure
stable excitation-contraction coupling cycles, are not precisely
known. However, the same mechanism leading to refractoriness of SR
Ca$^2+$ release could also be responsible for the termination
of CICR. To examine the refractoriness of SR Ca$^2+$ release,
we analyzed Na$^+$-Ca$^2+$ exchange currents reflecting cytosolic
Ca$^2+$ signals induced by UV-laser flash-photolysis of caged
Ca$^2+$. Pairs of UV flashes were applied at various intervals
to examine the time course of recovery from CICR refractoriness.
In cardiomyocytes isolated from guinea-pigs and mice, beta-adrenergic
stimulation with isoproterenol-accelerated recovery from refractoriness
by approximately 2-fold. Application of cyclopiazonic acid at moderate
concentrations (<10 micromol/L) slowed down recovery from refractoriness
in a dose-dependent manner. Compared with cells from wild-type littermates,
those from phospholamban knockout (PLB-KO) mice exhibited almost
5-fold accelerated recovery from refractoriness. Our results suggest
that SR Ca$^2+$ refilling mediated by the SR Ca$^2+$-pump
corresponds to the rate-limiting step for recovery from CICR refractoriness.
Thus, the Ca$^2+$ sensitivity of CICR appears to be regulated
by SR Ca$^2+$ content, possibly resulting from a change in the
steady-state Ca$^2+$ sensitivity and in the gating kinetics of
the SR Ca$^2+$ release channels (ryanodine receptors). During
Ca$^2+$ release, the concomitant reduction in Ca$^2+$ sensitivity
of the ryanodine receptors might also underlie Ca$^2+$ spark
termination by deactivation.
- 15388639
- acetic
- acids,
- animals,
- atpase,
- caffeine,
- calcium
- calcium,
- calcium-binding
- cardiac,
- channel
- channel,
- contraction,
- ethylenediamines,
- exchanger,
- gating,
- gov't,
- guinea
- indoles,
- ion
- isoproterenol,
- knockout,
- mice,
- myocardial
- myocardium,
- myocytes,
- non-p.h.s.,
- non-u.s.
- p.h.s.,
- patch-clamp
- photolysis,
- pigs,
- proteins,
- rays,
- receptor
- release
- research
- reticulum,
- ryanodine
- sarcoplasmic
- signaling,
- sodium-calcium
- support,
- techniques,
- u.s.
- ultraviolet
- {c}a$^{2+}$-transporting
Nutzer