Figure 3. Predicted time course of... | Rockefeller University Press

Figure 3.

Predicted time course of parameters associated with Ca2+release in mammalian muscle fibers following sudden, DHPR-activation-dependent reduction of Mg2+inhibition at Ca2+/Mg2+I1-sites ofcRyR1s in the presence of BAPTA. (A and B) Predicted time course of [Ca2+(t)]js, [Ca2+]SR, and SR Ca 2+ release flux into the cytosol upon DHPR-activation-dependent reduction of Mg2+ inhibition at Ca2+/Mg2+ I1 sites of cRyR1s in the presence of 10 mM BAPTA for ionic conditions at rest that are same as in the absence of BAPTA and SR was loaded with Ca2+ at endogenous level ([Ca2+]SR = 400 µM) prior to stimulation. The orange line in B shows [Ca2+(0)]SR. (C and D) Predictions for severely depleted SR of Ca2+ at the time of stimulation ([Ca2+]SR(0) = 100 µM) in the presence of 10 mM BAPTA. The cationic conditions in the JS at time of stimulation for trace a in C and for both traces in D were the same as those at rest used for panel A and B to ensure that the Ca2+ buffering capacity of 10 mM BAPTA in the JS was same at time of stimulation when the SR was endogenously loaded or severely depleted of Ca2+. For comparison purposes, trace b in C shows the time course of [Ca2+(t)]js when [Ca2+]SR(0) = 100 µM in the absence of BAPTA. The inset in D shows the SR Ca2+-release flux into the cytosol when the SR at rest is severely depleted of Ca2+. (E) Simulation of the time course of [Ca2+]SR in a muscle fiber with depleted SR at the time of stimulation ([Ca2+]SR(0) = 100 µM) in a solution of elevated ionic strength that increased Kin (and 4pKin) from 0.05 to 0.25 mM in the presence of 20 mM BAPTA and 20 nM [Ca2+]c (see text). The increased Kin reduces inhibition at the Ca2+/Mg2+ I1 sites at rest and increases the SR Ca2+ leak into the JS despite the reduction in [Ca2+]SR from 400 to 100 µM causing [Ca2+]js to rise to 1.6 μM at time of stimulation. Under these conditions, the sudden 30-fold DHPR-activation-induced rise of 4pKin to 7.5 mM causes SR Ca2+ release with no significant delay, despite severe SR Ca2+ depletion.

Predicted time course of parameters associated with Ca ²⁺ release in mammalian muscle fibers following sudden, DHPR-activation-dependent reduction of Mg ²⁺ inhibition at Ca ²⁺ /Mg ²⁺ I1-sites of ^c RyR1s in the presence of BAPTA. (A and B) Predicted time course of [Ca²⁺(t)]_js, [Ca²⁺]_SR, and SR Ca ²⁺ release flux into the cytosol upon DHPR-activation-dependent reduction of Mg²⁺ inhibition at Ca²⁺/Mg²⁺ I1 sites of ^cRyR1s in the presence of 10 mM BAPTA for ionic conditions at rest that are same as in the absence of BAPTA and SR was loaded with Ca²⁺ at endogenous level ([Ca²⁺]_SR = 400 µM) prior to stimulation. The orange line in B shows [Ca²⁺(0)]_SR. (C and D) Predictions for severely depleted SR of Ca²⁺ at the time of stimulation ([Ca²⁺]_SR(0) = 100 µM) in the presence of 10 mM BAPTA. The cationic conditions in the JS at time of stimulation for trace a in C and for both traces in D were the same as those at rest used for panel A and B to ensure that the Ca²⁺ buffering capacity of 10 mM BAPTA in the JS was same at time of stimulation when the SR was endogenously loaded or severely depleted of Ca²⁺. For comparison purposes, trace b in C shows the time course of [Ca²⁺(t)]_js when [Ca²⁺]_SR(0) = 100 µM in the absence of BAPTA. The inset in D shows the SR Ca²⁺-release flux into the cytosol when the SR at rest is severely depleted of Ca²⁺. (E) Simulation of the time course of [Ca²⁺]_SR in a muscle fiber with depleted SR at the time of stimulation ([Ca²⁺]_SR(0) = 100 µM) in a solution of elevated ionic strength that increased K_in (and ^4pK_in) from 0.05 to 0.25 mM in the presence of 20 mM BAPTA and 20 nM [Ca²⁺]_c (see text). The increased K_in reduces inhibition at the Ca²⁺/Mg²⁺ I1 sites at rest and increases the SR Ca²⁺ leak into the JS despite the reduction in [Ca²⁺]_SR from 400 to 100 µM causing [Ca²⁺]_js to rise to 1.6 μM at time of stimulation. Under these conditions, the sudden 30-fold DHPR-activation-induced rise of ^4pK_in to 7.5 mM causes SR Ca²⁺ release with no significant delay, despite severe SR Ca²⁺ depletion.

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