title: 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.
abstract: 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.
authors.affiliation: Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Guo
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: C503464:CaMKII inhibitor AIP; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D010455:Peptides; C489863:myristoylated autocamtide-2-related inhibitory peptide; D004533:Egtazic Acid; D019284:Thapsigargin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium