Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx.

Xiao, Rui‐Ping; Cheng, Heping; Lederer, W. J.; Suzuki, Tatsuo; Lakatta, Edward G.

doi:10.1073/pnas.91.20.9659

Cited by 179 publications

(154 citation statements)

References 24 publications

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“…Before ␣ 1 ARS, active CaMKII was detectable at the plasmalemma (Fig. 4 A and E) as reported (17). After ␣ 1 ARS (100 M phenylephrine) active CaMKII was still present at the plasmalemma (Fig.…”

Section: Effect Of 10 M Phenylephrine On Ical Measured By Using Thesupporting

confidence: 49%

“…It has been reported that CaMKII may directly phosphorylate the L-type Ca 2ϩ channel and regulate the positive feedback system that facilitates I Ca,L under physiological conditions (17,26). Our biochemical experiments showed that CaMKII is significantly activated by ␣ 1 ARS in adult rat isolated ventricular myocytes.…”

Section: Effect Of 10 M Phenylephrine On Ical Measured By Using Thementioning

confidence: 55%

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α ₁ -Adrenoceptor stimulation potentiates L-type Ca ²⁺ current through Ca ²⁺ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

O‐Uchi

Komukai

Kusakari

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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α 1 -Adrenoceptor stimulation (α 1 ARS) modulates cardiac muscle contraction under physiological conditions by means of changes in Ca 2+ current through L-type channels (I Ca,L ) and Ca 2+ ensitivity of the myofilaments. However, the cellular mechanisms of α 1 ARS are not fully clarified. In this study, we investigated the role of Ca 2+ /calmodulin-dependent PK II (CaMKII) in the regulation of I Ca,L during α 1 ARS in isolated adult rat ventricular myocytes by using the perforated patch–clamp technique. CaMKII inhibition with 0.5 μM KN-93 abolished the potentiation in I Ca,L observed during α 1 ARS by 10 μM phenylephrine. In the presence of PKC inhibitor (10 μM chelerythrine), the potentiation of I Ca,L by phenylephrine also disappeared. In Western immunoblotting analysis, phenylephrine (≥1 μM) increased the amount of autophosphorylated CaMKII (active CaMKII) significantly, and this increase was abolished by CaMKII inhibition or PKC inhibition. Also, we investigated changes in the subcellular localization of active CaMKII by using immunofluorescence microscopy and immunoelectron microscopy. Before α 1 ARS, active CaMKII was exclusively located just beneath the plasmalemma. However, after α 1 ARS, active CaMKII was localized close to transverse tubules, where most of L-type Ca 2+ channels are located. From these results, we propose that CaMKII, which exists near transverse tubules, is activated and phosphorylated by α 1 ARS and that CaMKII activation directly potentiates I Ca,L in rat ventricular myocytes.

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Section: Effect Of 10 M Phenylephrine On Ical Measured By Using Thesupporting

confidence: 49%

Section: Effect Of 10 M Phenylephrine On Ical Measured By Using Thementioning

confidence: 55%

α ₁ -Adrenoceptor stimulation potentiates L-type Ca ²⁺ current through Ca ²⁺ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

O‐Uchi

Komukai

Kusakari

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…It requires CaMKII-dependent phosphorylation, presumably of the α 1c -subunit or an associated protein [21,23,24]. Consequently, global CaMKII inhibition abolishes facilitation [22,24,34,51].…”

Section: Ca Facilitation Is Inhibited By Sr-targeted Camkii Inhibitionmentioning

confidence: 99%

“…CaMKII also mediates I Ca facilitation, where repeated depolarizations cause a Ca 2+ -and CaMKII-dependent increase in I Ca amplitude and slowing of inactivation [21][22][23][24]. As the Ltype Ca 2+ channel is in the sarcolemma, one might expect that SR localized AIP would not interfere with CaMKII mediated I Ca regulation.…”

Section: Introductionmentioning

confidence: 99%

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

Picht

DeSantiago

Huke

et al. 2007

Journal of Molecular and Cellular Cardiology

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Cardiac Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) in heart has been implicated in Ca 2+ current (I Ca ) facilitation, enhanced sarcoplasmic reticulum (SR) Ca2+ release and frequency dependent acceleration of relaxation (FDAR) via enhanced SR Ca 2+ uptake. However, questions remain about how CaMKII may work in these three processes. Here we tested the role of CaM-KII in these processes using transgenic mice (SR-AIP) that express four concatenated repeats of the CaMKII inhibitory peptide AIP selectively in the SR membrane. Wild type mice (WT) and mice expressing AIP exclusively in the nucleus (NLS-AIP) served as controls. Increasing stimulation frequency produced typical FDAR in WT and NLS-AIP, but FDAR was markedly inhibited in SR-AIP. Quantitative analysis of cytosolic Ca 2+ removal during [Ca 2+ ] i decline revealed that FDAR is due to an increased apparent V max of SERCA. CaMKII dependent RyR phosphorylation at Ser2815 and SR Ca 2+ leak were both decreased in SR-AIP vs. WT. This decrease in SR Ca 2+ leak may partly balance the reduced SERCA activity leading to relatively unaltered SR-Ca 2+ load in SR-AIP vs. WT myocytes. Surprisingly, CaMKII regulation of the L-type Ca 2+ channel (I Ca facilitation and recovery from inactivation) was abolished by the SR-targeted CaM-KII inhibition in SR-AIP mice. Inhibition of CaMKII effects on I Ca and RyR function by the SR-localized AIP places physical constraints on the localization of these proteins at the junctional microdomain. Thus SR-targeted CaMKII inhibition can directly inhibit the activation of SR Ca 2+ uptake, SR Ca 2+ release and I Ca by CaMKII, effects which have all been implicated in triggered arrhythmias.

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“…In the cardiovascular system, PKA and PKC are both known to affect heart rate, 26,27 and PKA, 28,29 PKC, 30 -33 protein kinase G, 28,34 and CaM kinase 10,13,14,[35][36][37] all participate in the regulation of smooth and cardiac muscle [Ca 2ϩ ] i . Thus, the acute hemodynamic response to the systemic application of these inhibitory agents could be an important limitation in the development of novel approaches to antiarrhythmic therapy with the use of serine/threonine kinase inhibitory agents.…”

Section: Serine/threonine Kinases In Cardiovascular Systemmentioning

confidence: 99%

Systemic Administration of Calmodulin Antagonist W-7 or Protein Kinase A Inhibitor H-8 Prevents Torsade de Pointes in Rabbits

Mazur¹,

Roden²,

Anderson³

1999

Circulation

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Background-The ventricular arrhythmia torsade de pointes (TdP) occurs after QT interval prolongation and is associated with sudden cardiac death. The afterdepolarizations that initiate TdP are facilitated by protein kinase A and the multifunctional Ca 2ϩ /calmodulin-dependent protein kinase II (CaM kinase). Methods and Results-In this study, we evaluated the feasibility of suppression of TdP through systemic therapy with kinase inhibitory agents in an established animal model. Under control conditions, TdP was inducible in 6 of 8 rabbits.CaM kinase blockade with the calmodulin antagonist W-7 reduced TdP in a dose-dependent fashion (4 of 7 inducible at 25 mol/kg and 1 of 7 inducible at 50 mol/kg). Increased intracellular Ca 2ϩ has been implicated in the genesis of afterdepolarizations, but pretreatment with high-dose W-7 did not prevent TdP in response to the L-type Ca 2ϩ channel agonist BAY K 8644 (300 nmol/kg), suggesting that CaM kinase-independent activation of L-type Ca 2ϩ current was not affected by W-7. Compared with control animals, W-7 reduced TdP inducibility without shortening the QT interval, increasing heart rate, or reducing the blood pressure. The protein kinase A antagonist H-8 also caused a dose-dependent reduction in TdP inducibility (5 of 6 at 1 mol/kg, 4 of 6 at 5 mol/kg, and 0 of 6 at 10 mol/kg), but unlike W-7, H-8 did so by shortening the QT interval. Conclusions-These findings show that the acute systemic application of W-7 and H-8 is hemodynamically tolerated and indicate that kinase inhibition may be a viable antiarrhythmic strategy. (Circulation. 1999;100:2437-2442.)

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Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx.

Cited by 179 publications

References 24 publications

α ₁ -Adrenoceptor stimulation potentiates L-type Ca ²⁺ current through Ca ²⁺ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

α ₁ -Adrenoceptor stimulation potentiates L-type Ca ²⁺ current through Ca ²⁺ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

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

Systemic Administration of Calmodulin Antagonist W-7 or Protein Kinase A Inhibitor H-8 Prevents Torsade de Pointes in Rabbits

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Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane voltage and by calcium influx.

Cited by 179 publications

References 24 publications

α 1 -Adrenoceptor stimulation potentiates L-type Ca 2+ current through Ca 2+ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

α 1 -Adrenoceptor stimulation potentiates L-type Ca 2+ current through Ca 2+ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

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

Systemic Administration of Calmodulin Antagonist W-7 or Protein Kinase A Inhibitor H-8 Prevents Torsade de Pointes in Rabbits

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α ₁ -Adrenoceptor stimulation potentiates L-type Ca ²⁺ current through Ca ²⁺ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes

α ₁ -Adrenoceptor stimulation potentiates L-type Ca ²⁺ current through Ca ²⁺ /calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes