Inactivation of ICa-L is the major determinant of use-dependent facilitation in rat cardiomyocytes.
Two models have been proposed to explain facilitation of the L-type calcium current (ICa-L). A positive feedback model proposes that calcium released during a conditioning pulse (I1) facilitates the subsequent pulse (I2) via calmodulin/calmodulin kinase II (CaMKII) mechanisms. The negative feedback model proposes that the calcium release of each pulse feeds back on itself via calcium-dependent inactivation. The relative physiological roles were evaluated in rat ventricular myocytes. Paired pulses (450 ms interpulse interval) elicited facilitation (I2 of 872 +/- 145 versus I1 of 777 +/- 132 pA, P < 0.01). Inactivation time (T0.37) was prolonged for I2 versus I1 (22 +/- 2 and 16 +/- 2 ms, P > 0.01). Evidence for the negative feedback mechanism includes: (a) ryanodine (0.3 mM ) eliminated facilitation, surprisingly by increasing the amplitude of I1 more than that of I2 (1039 +/- 216 and 977 +/- 186 pA) and eliminated the difference in T0.37 between I2 and I1 (33.1 +/- 4.5 versus 32.5 +/- 4.6 ms); (b) an outward I2, which does not trigger sarcoplasmic reticulum (SR) Ca2+ release, eliminated facilitation even when it was conditioned by an inward I1; (c) facilitation decayed as the I1-I2 interval lengthened (time constant (tau) = 16.9 +/- 1.4 s); (d) thapsigargin (0.1 microM ) slowed this decay (tau = 43.8 +/- 11.7 s) whereas isoproterenol accelerated it (tau = 5.6 +/- 1.4 s, P < 0.01) and T0.37 paralleled this decay; and (e) the magnitude of ICa-L was negatively correlated with the sodium-calcium exchange current (INa/Ca) elicited by the SR-Ca2+ release. In conclusion, Ca2+-dependent inactivation of ICa-L is the major mechanism underlying facilitation.
Guo
J
J
Department of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Duff
H J
HJ
D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008297:Male; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019284:Thapsigargin / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D012433:Ryanodine; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases