Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations: a simple model

Dupont, Geneviève; Houart, Gérald; Koninck, Paul De

doi:10.1016/s0143-4160(03)00152-0

Cited by 132 publications

(156 citation statements)

References 60 publications

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“…The activity of CaMKII is regulated in response to frequency and amplitude of Ca 2+ transients [38,39]. At low stimulation frequencies CaMKII mediated phosphorylation is small but increases substantially at high frequencies [14,40,41].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Just as the activity of a nerve is conveyed by the frequency of its action potentials, Cobbold demonstrated that in hepatocytes the concentration of the extracellular stimulus determined the frequency of the cytosolic Ca 2þ transients. As these ideas gathered momentum (Berridge 1995), evidence accumulated in support of cells using the information provided by frequency-encoded Ca 2þ spikes as an efficient means of regulating cellular activity (Dolmetsch et al 1997;Li et al 1998;Berridge et al 2000;Dupont et al 2003). The single greatest contributor to progress in understanding the genesis of these intracellular Ca 2þ signals was the introduction, by Roger Tsien in 1980, of simple, minimally disruptive methods for measuring the free cytosolic Ca 2þ concentration in intact cells (Tsien 1980;Tsien 1981).…”

Section: Ip 3 Receptorsmentioning

confidence: 99%

IP3 Receptors: Toward Understanding Their Activation

Taylor¹,

Tovey²

2010

Cold Spring Harbor Perspectives in Biology

260

190

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Inositol 1,4,5-trisphosphate receptors (IP 3 R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca 2þ release from intracellular stores. Their regulation by Ca 2þ allows them also to propagate cytosolic Ca 2þ signals regeneratively. This brief review addresses the structural basis of IP 3 R activation by IP 3 and Ca 2þ . IP 3 initiates IP 3 R activation by promoting Ca 2þ binding to a stimulatory Ca 2þ -binding site, the identity of which is unresolved. We suggest that interactions of critical phosphate groups in IP 3 with opposite sides of the clam-like IP 3 -binding core cause it to close and propagate a conformational change toward the pore via the adjacent N-terminal suppressor domain. The pore, assembled from the last pair of transmembrane domains and the intervening pore loop from each of the four IP 3 R subunits, forms a structure in which a luminal selectivity filter and a gate at the cytosolic end of the pore control cation fluxes through the IP 3 R.

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“…To decode the information contained within Ca 2ϩ oscillations, cells have evolved a number of frequency-modulated decoders. Such proteins include calmodulin (10), protein kinase C (11-15), calpain (16), calmodulin-dependent protein kinase II (17,18), and the Ras GTPaseactivating protein RASAL (19).Ras proteins are binary molecular switches that regulate multiple signaling pathways, including those controlling growth and differentiation, through an ability to cycle between inactive GDP-and active GTP-bound conformations (20-23). The magnitude and duration of Ras signaling is controlled by two classes of proteins: Guanine nucleotide exchange factors modulate Ras activation by enhancing the exchange of GDP for GTP, and GTPase-activating proteins regulate inactivation by increasing the intrinsic Ras GTPase activity (20-23).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade

Kupzig

Walker

Cullen

2005

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

112

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Ras proteins are binary switches that, by cycling through inactive GDP-and active GTP-bound conformations, regulate multiple cellular signaling pathways, including those that control growth and differentiation. For some time, it has been known that receptormediated increases in the concentration of intracellular free calcium ( [Ca 2ϩ ] i is responsible for controlling a diverse array of cellular processes, including secretion, contraction, learning, and proliferation (3). Understanding how receptor-mediated increases in [Ca 2ϩ ] i are capable of modulating so many physiological processes is one of the major challenges in the study of Ca 2ϩ signaling. It appears that such control is achieved through a complex relationship between the amplitude and spatiotemporal patterning of the Ca 2ϩ signal and its resultant ability to couple to an extensive molecular repertoire of Ca 2ϩ -sensing proteins (3).Receptor-mediated increases in [Ca 2ϩ ] i are often observed as repetitive Ca 2ϩ spikes or oscillations that increase their frequency with the amplitude of the receptor stimuli (refs. 4 and 5; reviewed in ref. 3). These frequency-encoded signals appear to be critical for the induction of selective cellular functions (3). For example, the frequency of receptor-mediated Ca 2ϩ oscillations determines the efficiency of gene expression driven by the transcription factors NF-AT, OAP, and NF-B (6-8) and mitochondrial ATP production (9). To decode the information contained within Ca 2ϩ oscillations, cells have evolved a number of frequency-modulated decoders. Such proteins include calmodulin (10), protein kinase C (11-15), calpain (16), calmodulin-dependent protein kinase II (17,18), and the Ras GTPaseactivating protein RASAL (19).Ras proteins are binary molecular switches that regulate multiple signaling pathways, including those controlling growth and differentiation, through an ability to cycle between inactive GDP-and active GTP-bound conformations (20-23). The magnitude and duration of Ras signaling is controlled by two classes of proteins: Guanine nucleotide exchange factors modulate Ras activation by enhancing the exchange of GDP for GTP, and GTPase-activating proteins regulate inactivation by increasing the intrinsic Ras GTPase activity (20-23). Although it has been known for some time that increases in [Ca 2ϩ ] i can modulate Ras activation (for example, Ca 2ϩ influx through voltage-operated ion channels or release from internal stores can activate Ras in neuronal cells) (24), only recently have molecular entities been described that allow for this coupling (reviewed in ref. 25).Two families of Ras guanine nucleotide exchange factors (GEFs), and RasGRPs (30-36), the latter also being known as CalDAG-GEFs, are modulated by increases in [Ca 2ϩ ] i . For RasGRFs, this modulation occurs indirectly through association with Ca 2ϩ ͞calmodulin, whereas for RasGRPs, a more direct control is achieved through association of Ca 2ϩ with atypical EF hands (25). In addition to stimulating Ras activation, increases in [Ca 2ϩ ] i ...

show abstract

Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations: a simple model

Cited by 132 publications

References 60 publications

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

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

IP3 Receptors: Toward Understanding Their Activation

The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade

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