NUMERICAL-ANALYSIS OF RYANODINE RECEPTOR ACTIVATION BY L-TYPE CHANNELACTIVITY IN THE CARDIAC-MUSCLE DIAD

Computer simulations were used to examine the response of ryanodine re ceptors (RyRs) to the sarcolemmal calcium influx via L-type calcium ch annels (DHPRs), The effects of ryanodine receptor organization, diad g eometry, DHPR single-channel current, and DHPR gating were examined, I n agreement with experimental findings, the simulations showed that Ry Rs can respond rapidly (similar to 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 gen erally less responsive. When the DHPR single-channel current is small (similar to 25 fA), the organization of RyRs into small clusters resul ts in an improved responsiveness. With experimentally observed DHPR me an open and closed times (0.17 ms and 4 ms, respectively) it is the fi rst opening of the DHPR that is most likely to activate the RyR. A mea sure of the efficiency (Q) by which DHPR gating evokes sarcoplasmic re ticulum release is defined. Q is at maximum for tau approximate to 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 w ith a mismatch in the ''tuning,'' then modification of DHPR gating wit h drugs to ''retune'' calcium-induced calcium release should be possib le.