Calmodulin kinase II accelerates L-type Ca2+ current recovery from inactivation and compensates for the direct inhibitory effect of [Ca2+]i in rat ventricular myocytes.

Some studies report that the positive relationship between L-type Ca(2+) current (I(Ca-L)) and frequency in cardiac myocytes is mainly due to a direct negative feedback of sarcoplasmic reticulum Ca(2+) release on I(Ca-L) inactivation while others provide evidence for activation of calmodulin kinase II (CaMKII). To further elucidate the role of endogenous CaMKII activity, the CaMKII inhibitory peptides, autocamtide-2 relating inhibitory peptide (AIP) and myristoylated AIP were applied using conventional and perforated patch-clamp methods. AIP inhibited the normal adaptive increase in I(Ca-L) in response to abrupt increase in pacing frequency from 0.05 to 2 Hz. The positive I(Ca-L)-frequency relationship was reversed by AIP and the inhibitory effect of AIP was significantly exaggerated at fast pacing rates. The onset of inactivation of I(Ca-L) was not altered by AIP. After thapsigargin treatment, AIP slowed recovery from inactivation of I(Ca-L) and this effect was exaggerated during fast pacing. Buffering of [Ca(2+)](i) by BAPTA and EGTA accelerated recovery of I(Ca-L) from inactivation, and BAPTA partly eliminated the effect of AIP on the recovery. We conclude that: (1) [Ca(2+)](i) directly slows I(Ca-L) recovery from inactivation; and (2) Ca(2+)-dependent endogenous CaMKII activity accelerates the I(Ca-L) recovery. Thus, at fast heart rates, elevated [Ca(2+)](i) activates endogenous CaMKII and compensates for its direct inhibitory effect on I(Ca-L) recovery from inactivation. Dynamic activity of endogenous CaMKII enhances the positive I(Ca-L)-frequency relationship.