Abstract
In heart, a robust regulatory mechanism is required to counteract
the regenerative Ca$^2+$-induced Ca$^2+$ release from the
sarcoplasmic reticulum. Several mechanisms, including inactivation,
adaptation, and stochastic closing of ryanodine receptors (RyRs)
have been proposed, but no conclusive evidence has yet been provided.
We probed the termination process of Ca$^2+$ release by using
a technique of imaging local Ca$^2+$ release, or "Ca$^2+$
spikes", at subcellular sites; and we tracked the kinetics of Ca$^2+$
release triggered by L-type Ca$^2+$ channels. At 0 mV, Ca$^2+$
release occurred and terminated within 40 ms after the onset of clamp
pulses (0 mV). Increasing the open-duration and promoting the reopenings
of Ca$^2+$ channels with the Ca$^2+$ channel agonist, FPL64176,
did not prolong or trigger secondary Ca$^2+$ spikes, even though
two-thirds of the sarcoplasmic reticulum Ca$^2+$ remained available
for release. Latency of Ca$^2+$ spikes coincided with the first
openings but not with the reopenings of L-type Ca$^2+$ channels.
After an initial maximal release, even a multi-fold increase in unitary
Ca$^2+$ current induced by a hyperpolarization to -120 mV failed
to trigger additional release, indicating absolute refractoriness
of RyRs. When the release was submaximal (e.g., at +30 mV), tail
currents did activate additional Ca$^2+$ spikes; confocal images
revealed that they originated from RyRs unfired during depolarization.
These results indicate that Ca$^2+$ release is terminated primarily
by a highly localized, use-dependent inactivation of RyRs but not
by the stochastic closing or adaptation of RyRs in intact ventricular
myocytes.
- 9844021
- agonists,
- analysis,
- and
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- calcium,
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- nonlinear
- p.h.s.,
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- rumen,
- ryanodine
- soybeans,
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- wistar,
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