The effect of Ca2+-calmodulin-dependent protein kinase II on cardiac excitation-contraction coupling in ferret ventricular myocytes

Li Li, Hiroshi Satoh, Kenneth S Ginsburg, Donald M Bers

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144 Scopus citations


1. The effect of Ca2+-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 caffeine 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 Ca(o)2+), 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 (τ) 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 I-type Ca2+ current (I(Ca)) 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 I(Ca) 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 I(Ca), we infer that endogenous CaMKII is an important modulator of E-C coupling in intact cardiac myocytes. Effects of KN-93 on I(Ca) and SS twitch [Ca2+](i) decline also indicate that endogenous CaMKII may have stimulatory effects on I(Ca) and SR Ca2+ uptake.

Original languageEnglish (US)
Pages (from-to)17-31
Number of pages15
JournalJournal of Physiology
Issue number1
StatePublished - May 15 1997
Externally publishedYes

ASJC Scopus subject areas

  • Physiology


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