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Calmodulin kinase II accelerates L‐type Ca 2+ current recovery from inactivation and compensates for the direct inhibitory effect of [Ca 2+ ] i in rat ventricular myocytes
Author(s) -
Guo Jiqing,
Duff Henry J.
Publication year - 2006
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.109199
Subject(s) - inhibitory postsynaptic potential , calmodulin , chemistry , biophysics , biochemistry , biology , enzyme , endocrinology
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.