Abstract
Computer simulations were used to examine the response of ryanodine
receptors (RyRs) to the sarcolemmal calcium influx via L-type calcium
channels (DHPRs). The effects of ryanodine receptor organization,
diad geometry, DHPR single-channel current, and DHPR gating were
examined. In agreement with experimental findings, the simulations
showed that RyRs can respond rapidly (approximately 0.4 ms) to calcium
influx via DHPRs. The responsiveness of the RyR depends on the geometrical
arrangement between the RyRs and the DHPR in the diad, with wider
diads being generally less responsive. When the DHPR single-channel
current is small (approximately 25 fA), the organization of RyRs
into small clusters results in an improved responsiveness. With experimentally
observed DHPR mean open and closed times (0.17 ms and 4 ms, respectively)
it is the first opening of the DHPR that is most likely to activate
the RyR. A measure of the efficiency (Q) by which DHPR gating evokes
sarcoplasmic reticulum release is defined. Q is at maximum for tau
approximately 0.3 ms, and we interpret this finding in terms of the
"tuning" of DHPR gating to RyR response. If certain cardiac myopathies
are associated with a mismatch in the "tuning," then modification
of DHPR gating with drugs to "retune" calcium-induced calcium release
should be possible.
- 9199776
- calcium
- calcium,
- cardiovascular,
- channel
- channel,
- channels,
- computer
- factors,
- gating,
- gov't,
- heart,
- ion
- kinetics,
- l-type,
- mathematics,
- models,
- muscle
- myocardium,
- non-u.s.
- proteins,
- receptor
- release
- research
- ryanodine
- signal
- simulation,
- support,
- time
- transduction,
- transport,
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