Ra. Bassani et al., CAMKII IS RESPONSIBLE FOR ACTIVITY-DEPENDENT ACCELERATION OF RELAXATION IN RAT VENTRICULAR MYOCYTES, American journal of physiology. Heart and circulatory physiology, 37(2), 1995, pp. 703-712
We investigated the role of Ca/calmodulin-dependent protein kinase (Ca
MKII) in relaxation and cytosolic free [Ca] ([Ca](i)) decline during s
teady-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 reticu
lum (SR) Ca accumulation by thapsigargin or caffeine; 2) greater at hi
gher stimulation frequency and extracellular [Ca], which affected only
SS tau; 3) abolished by the protein phosphatase inhibitor okadaic aci
d (10 mu M, which selectively accelerated [Ca]i decline during PR); 4)
still present during stimulation or inhibition of adenosine 3',5'-cyc
lic monophosphate-dependent protein kinase (PKA) by 10 mu M forskolin
or 1 mu M H-89, respectively (SS and PR tau values were abbreviated an
d prolonged, respectively); and 5) suppressed by 10 mu M KN-62, a sele
ctive 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 myocyte
s. We conclude that CaMKII plays a major role in modulation of relaxat
ion 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.