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Inactivation of I Ca‐L is the major determinant of use‐dependent facilitation in rat cardiomyocytes
Author(s) -
Guo J.,
Duff H. J.
Publication year - 2003
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.2003.00797.x
Subject(s) - facilitation , neuroscience , chemistry , biology , psychology
Two models have been proposed to explain facilitation of the L‐type calcium current ( I Ca‐L ). A positive feedback model proposes that calcium released during a conditioning pulse ( I 1 ) facilitates the subsequent pulse ( I 2 ) 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 ( I 2 of 872 ± 145 versus I 1 of 777 ± 132 pA, P < 0.01). Inactivation time ( T 0.37 ) was prolonged for I 2 versus I 1 (22 ± 2 and 16 ± 2 ms, P > 0.01). Evidence for the negative feedback mechanism includes: (a) ryanodine (0.3 m m ) eliminated facilitation, surprisingly by increasing the amplitude of I 1 more than that of I 2 (1039 ± 216 and 977 ± 186 pA) and eliminated the difference in T 0.37 between I 2 and I 1 (33.1 ± 4.5 versus 32.5 ± 4.6 ms); (b) an outward I 2 , which does not trigger sarcoplasmic reticulum (SR) Ca 2+ release, eliminated facilitation even when it was conditioned by an inward I 1 ; (c) facilitation decayed as the I 1 – I 2 interval lengthened (time constant (τ) = 16.9 ± 1.4 s); (d) thapsigargin (0.1 μ m ) slowed this decay (τ= 43.8 ± 11.7 s) whereas isoproterenol accelerated it (τ> = 5.6 ± 1.4 s, P < 0.01) and T 0.37 paralleled this decay; and (e) the magnitude of I Ca‐L was negatively correlated with the sodium‐calcium exchange current ( I Na/Ca ) elicited by the SR‐Ca 2+ release. In conclusion, Ca 2+ ‐dependent inactivation of I Ca‐L is the major mechanism underlying facilitation.