The effect of Ca2+–calmodulin‐dependent protein kinase II on cardiac excitation–contraction coupling in ferret ventricular myocytes
L Li, H Satoh, KS Ginsburg… - The Journal of physiology, 1997 - Wiley Online Library
L Li, H Satoh, KS Ginsburg, DM Bers
The Journal of physiology, 1997•Wiley Online Library1 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 …
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 …
- 1The 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%).
- 2Increasing 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 Cao2+), but SS twitch [Ca2+]i was still significantly depressed by KN‐93.
- 3KN‐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.
- 4Voltageclamp 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.
- 5In 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).
- 6Since 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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