CaMKII tethers to L-type Ca2<b>+</b> channels, establishing a local and dedicated integrator of Ca2<b>+</b> signals for facilitation

Hudmon, Andy; Schulman, Howard; Kim, James; Maltez, Janet M; Tsien, Richard W.; Pitt, Geoffrey S.

doi:10.1083/jcb.200505155

Cited by 315 publications

(325 citation statements)

References 72 publications

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“…One of the most intriguing properties of this kinase is its ability to form large aggregates in neuronal dendrites and soma under a variety of conditions (6,7,12,40,41). The formation of these aggregates is isozyme-specific and is believed to be regulated by pH and ATP concentration.…”

Section: Discussionmentioning

confidence: 99%

Ischemia-elicited Oxidative Modulation of Ca2+/Calmodulin-dependent Protein Kinase II

Shetty

Huang

2008

Journal of Biological Chemistry

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Ca 2؉ /calmodulin (CaM)-dependent protein kinase II (CaMKII) plays a critical role in neuronal signal transduction and synaptic plasticity. Here, we showed that this kinase was very susceptible to oxidative modulation. Treatment of mouse brain synaptosomes with H 2 O 2 , diamide, and sodium nitroprusside caused aggregation of CaMKII through formation of disulfide and non-disulfide linkages, and partial inhibition of the kinase activity. These CaMKII aggregates were found to associate with the post synaptic density. However, treatment of purified CaMKII with these oxidants did not replicate those effects observed in the synaptosomes. Using two previously identified potential mediators of oxidants in the brain, glutathione disulfide S-monoxide (GS-DSMO) and glutathione disulfide S-dioxide (GS-DSDO), we showed that they oxidized and inhibited CaMKII in a manner partly related to those of the oxidanttreated synaptosomes as well as the ischemia-elicited oxidative stress in the acutely prepared hippocampal slices. Interestingly, the autophosphorylated and activated CaMKII was relatively refractory to GS-DSMO-and GS-DSDO-mediated aggregation. Short term ischemia (10 min) caused a depression of basal synaptic response of the hippocampal slices, and re-oxygenation (after 10 min) reversed the depression. However, oxidation of CaMKII remained at above the pre-ischemic level throughout the treatment. Oxidation of CaMKII also prevented full recovery of CaMKII autophosphorylation after re-oxygenation. Subsequently, the high frequency stimulation-mediated synaptic potentiation in the hippocampal CA1 region was significantly reduced compared with the control without ischemia. Thus, ischemia-evoked oxidation of CaMKII, probably via the action of glutathione disulfide S-oxides or their analogues, may be involved in the suppression of synaptic plasticity.Ca 2ϩ /calmodulin (CaM) 2 -dependent protein kinase II (CaMKII) is one of the major Ca 2ϩ -sensing enzymes important in transducing neuronal, hormonal, and electrical signals in brain, heart, and other tissues. In the central nervous system, CaMKII plays a pivotal role in the facilitation of synaptic plasticity, learning, and memory and in activity-dependent developmental processes (1). CaMKII holoenzyme is a dodecamer composed of two stacked hexameric rings, in which each catalytic/regulatory domain from the upper ring interacts with the equivalent catalytic/regulatory domain in the lower ring by an antiparallel coiled-coil, which resides in regulatory domains (2). Binding of Ca 2ϩ /CaM to the regulatory domain separates the dimer pair and causes the exposure of Thr-286 or Thr-287 (within ␣ or ␤ subunit) for phosphorylation by another catalytic domain in the same ring. This inter-subunit phosphorylation of Thr-286/287 converts the kinase into a high affinity binding protein for Ca 2ϩ /CaM, and the kinase becomes an activatorindependent autonomous enzyme (3). The autophosphorylation also leads to increased affinity of the kinase for several proteins near the sites of elevated Ca 2...

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Section: Discussionmentioning

confidence: 99%

Ischemia-elicited Oxidative Modulation of Ca2+/Calmodulin-dependent Protein Kinase II

Shetty

Huang

2008

Journal of Biological Chemistry

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“…CaMKII is known to associate with ryanodine receptors (RyRs) [3,4], L-type Ca 2+ channels [5][6][7] and possibly phospholamban (PLB) [8]. This basal localization near targets may be important for efficient and specific regulation of these CaMKII effector proteins.…”

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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“…''Mode 2'' gating was discovered as a pharmacological effect of the dihydropyridine Bay K8644 (4), but subsequent work has implicated reversible protein phosphorylation of the channel by calcium͞calmodulin-dependent protein kinase type II (CaMKII) in the regulation of mode 2 gating in cells that were not treated with dihydropyridines (5). Although the molecular mechanism of this effect and its physiological consequences are only beginning to be investigated (6)(7)(8)(9), it is likely that unregulated mode 2 gating would be cytotoxic because the individual channel openings in mode 2 are Ͼ10 times longer on average than the openings in mode 1.…”

mentioning

confidence: 99%

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Erxleben

Liao

Gentile

et al. 2006

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

105

116

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Calcium channels in the plasma membrane rarely remain open for much more than a millisecond at any one time, which avoids raising intracellular calcium to toxic levels. However, the dihydropyridinesensitive calcium channels of the CaV1 family, which selectively couple electrical excitation to endocrine secretion, cardiovascular contractility, and neuronal transcription, have a unique second mode of gating, ''mode 2,'' that involves frequent openings of much longer duration. Here we report that two human conditions, cyclosporin neurotoxicity and Timothy syndrome, increase mode 2 gating of the recombinant rabbit CaV1.2 channel. In each case, mode 2 gating depends on a Ser residue at the cytoplasmic end of the S6 helix in domain I (Ser-439, Timothy syndrome) or domain IV (Ser-1517, cyclosporin). Both Ser reside in consensus sequences for type II calmodulin-dependent protein kinase. Pharmacologically inhibiting type II calmodulin-dependent protein kinase or mutating the Ser residues to Ala prevents the increase in mode 2 gating. We propose that aberrant phosphorylation, or ''phosphorylopathy,'' of the CaV1.2 channel protein contributes to the excitotoxicity associated with Timothy syndrome and with chronic cyclosporin treatment of transplant patients.calcium͞calmodulin-dependent protein kinase type II ͉ calcineurin ͉ dihydropyridine ͉ excitotoxicity

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CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation

Cited by 315 publications

References 72 publications

Ischemia-elicited Oxidative Modulation of Ca2+/Calmodulin-dependent Protein Kinase II

Ischemia-elicited Oxidative Modulation of Ca2+/Calmodulin-dependent Protein Kinase II

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

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

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