CaMKII is responsible for activity-dependent acceleration of relaxation in rat ventricular myocytes

Abstract

We investigated the role of Ca/calmodulin-dependent protein kinase (CaMKII) in relaxation and cytosolic free [Ca] ([Ca]i) decline during steady-state (SS) and postrest (PR) twitches in intact rat ventricular myocytes. Half-time of mechanical relaxation and time constant of [Ca]i decline (tau) were twofold greater during PR than with SS at 1 Hz. This difference was 1) abolished by inhibition of sarcoplasmic reticulum (SR) Ca accumulation by thapsigargin or caffeine; 2) greater at higher stimulation frequency and extracellular [Ca], which affected only SS tau; 3) abolished by the protein phosphatase inhibitor okadaic acid (10 microM, which selectively accelerated [Ca]i decline during PR); 4) still present during stimulation or inhibition of adenosine 3',5'-cyclic monophosphate-dependent protein kinase (PKA) by 10 microM forskolin or 1 microM H-89, respectively (SS and PR tau values were abbreviated and prolonged, respectively); and 5) suppressed by 10 microM KN-62, a selective inhibitor of CaMKII, which selectively prolonged [Ca]i decline during SS twitches. Both protein kinase inhibitors were also shown to decrease the SR Ca-uptake rate in digitonin-permeabilized rat myocytes. We conclude that CaMKII plays a major role in modulation of relaxation in rat ventricular myocytes, enhancing SR Ca uptake in a activity-dependent fashion. Our results are also compatible with a background, activity-independent stimulation of SR Ca uptake by PKA in intact rat myocytes.

CaMKII inhibition targeted to the sarcoplasmic reticulum inhibits frequency-dependent acceleration of relaxation and Ca2+ current facilitation

“…Both relaxation and [Ca 2+ ] i decline rates are accelerated at higher frequency in all species studied and enhanced rate of SR Ca 2+ uptake appears to drive both effects [9][10][11][12]. Some reports have shown that FDAR can be strongly suppressed by CaMKII inhibitors (KN-93, KN-62, AIP) [9,[12][13][14], while other reports could not detect effects on FDAR of organic inhibitors or KN-62 [11,[15][16][17]. CaMKII-dependent PLB phosphorylation seemed a plausible FDAR mediator and some data seemed to support that [14,18].…”

“…The contribution of PLB and CaMKII to FDAR remains controversial. CaMKII inhibition has been reported to suppress FDAR in several studies [9,12,13], but other studies did not detect FDAR inhibition with KN-93 or KN-62 [11,[15][16][17]. In isolated myocytes CaMKII dependent phosphorylation of PLB at Thr17 occurs in a frequency dependent manner [14,17].…”

“…It results from accelerated SR Ca 2+ uptake and does not depend on Ca 2+ removal out of the cell [9,11,17]. The contribution of PLB and CaMKII to FDAR remains controversial.…”

Aerobic interval training enhances cardiomyocyte contractility and Ca2+ cycling by phosphorylation of CaMKII and Thr-17 of phospholamban

“…FDAR ensures appropriate ventricular filling at high heart rates, and results from accelerated SR Ca 2+ uptake independent of Ca 2+ removal out of the cell [27]. However, the contributions of PLB and CaMKII to FDAR remain controversial [28].…”

Mitochondrial‐Mediated Oxidative Ca 2+ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

“…A growing body of evidence has demonstrated that CaMKII can also be activated by ROS 21, 22, 23, 24. Once activated, CaMKII can phosphorylate a wide range of key Ca 2+ and Na + regulatory proteins such as LCCs,25, 26, 27, 28 RyRs,29, 30, 31, 32, 33, 34, 35 phosphalamban,29, 34, 36 and Na + channels 37, 38. Importantly, Xie et al39 showed that H 2 O 2 perfusion–induced oxidative CaMKII activation leads to afterdepolarizations in isolated rabbit cardiomyocytes, likely by phosphorylation of Na + channels and LCCs.…”