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. 1997 May 15;501(Pt 1):17–31. doi: 10.1111/j.1469-7793.1997.017bo.x

The effect of Ca(2+)-calmodulin-dependent protein kinase II on cardiac excitation-contraction coupling in ferret ventricular myocytes.

L Li 1, H Satoh 1, K S Ginsburg 1, D M Bers 1
PMCID: PMC1159500  PMID: 9174990

Abstract

1. The effect of Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) on excitation-contraction coupling (E-C coupling) was studied in intact ferret cardiac myocytes using the selective inhibitor KN-93, KN-93 decreased steady-state (SS) twitch [Ca2+]i (by 51%), resting Ca2+ spark frequency (by 88%) and SS sarcoplasmic reticulum (SR) Ca2+ content evaluated by eaffeine application (by 37.5%). 2. Increasing extracellular Ca2+ concentration ([Ca2+]o) to 5 mM in KN-93 restored SR Ca2+ load and Ca2+ spark frequency towards that in control (2 mM Ca2+o), but SS twitch [Ca2+]i was still significantly depressed by KN-93. 3. KN-93 decreased Ca2+ transient amplitude of SS twitches much more strongly than the amplitude of post-rest (PR) twitches. In the control, the time constant (Tau) of [Ca2+]i decline of SS twitches was faster than that for PR twitches. This stimulation-dependent acceleration of [Ca2+]i decline was abolished by KN-93. 4. Voltage-clamp experiments demonstrated that KN-93 significantly inhibited sarcolemmal L-type Ca2+ current (ICa) during repetitive pulses by slowing recovery from inactivation. This may explain the preferential action of KN-93 to suppress SS vs. PR twitches. 5. In KN-93, even when both ICa and SR Ca2+ load were matched to the control levels by manipulation of conditioning voltage-clamp pulses, contraction and twitch Ca2+ transients were still both significantly depressed (to 39 and 49% of control, respectively). 6. Since KN-93 reduced SR Ca2+ release channel (RyR) activity during E-C coupling, even for matched SR Ca2+ load and trigger ICa, we infer that endogenous CaMKII is an important modulator of E-C coupling in intact cardiac myocytes. Effects of KN-93 on ICa and SS twitch [Ca2+]i decline also indicate that endogenous CaMKII may have stimulatory effects on ICa and SR Ca2+ uptake.

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Selected References

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