Li2019 - Neurogranin stimulates Ca/calmodulin-dependent kinase II by inhibiting Calcineurin
Ontology highlight
ABSTRACT:
SUBMITTER: 
Lu Li
PROVIDER: MODEL1903010001 | BioModels | 2019-12-18
REPOSITORIES: BioModels
Similar Datasets
Project description:Li2012 Calcium mediated synaptic
plasticity
This model is an extension of
BIOMD0000000183.
This model is described in the article:
Calcium input frequency,
duration and amplitude differentially modulate the relative
activation of calcineurin and CaMKII.
Li L, Stefan MI, Le Novère
N.
PLoS ONE 2012; 7(9): e43810
Abstract:
NMDA receptor dependent long-term potentiation (LTP) and
long-term depression (LTD) are two prominent forms of synaptic
plasticity, both of which are triggered by post-synaptic
calcium elevation. To understand how calcium selectively
stimulates two opposing processes, we developed a detailed
computational model and performed simulations with different
calcium input frequencies, amplitudes, and durations. We show
that with a total amount of calcium ions kept constant, high
frequencies of calcium pulses stimulate calmodulin more
efficiently. Calcium input activates both calcineurin and
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) at all
frequencies, but increased frequencies shift the relative
activation from calcineurin to CaMKII. Irrespective of
amplitude and duration of the inputs, the total amount of
calcium ions injected adjusts the sensitivity of the system to
calcium input frequencies. At a given frequency, the quantity
of CaMKII activated is proportional to the total amount of
calcium. Thus, an input of a small amount of calcium at high
frequencies can induce the same activation of CaMKII as a
larger amount, at lower frequencies. Finally, the extent of
activation of CaMKII signals with high calcium frequency is
further controlled by other factors, including the availability
of calmodulin, and by the potency of phosphatase
inhibitors.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000628.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-12-10 | BIOMD0000000628 | BioModels
Project description:N6-methyladenosine (m6A) plays diverse roles in the regulation of mRNA metabolism. In the mammalian brain it has been linked to developmental processes, memory function and plasticity. However, the precise role of m6A in the context synaptic plasticity and especially during impaired cognition are not fully understood. Here, we describe the mouse and human brain m6A epi-transcriptome in a tissue-specific manner. We furthermore show that m6A levels undergo massive decreases across mouse brain regions as a consequence of aging. Equally, Alzheimer’s disease in humans correlates with decreased N6-methylation in a similar population of transcripts that are linked to synaptic function and localized to synapses, such as the calcium/calmodulin-dependent kinase II (CaMKII). In line with this we show that reduced m6A levels impair synaptic protein-synthesis of CAMKII. Our results suggest that N6-RNA-methylation is an important mechanism to control synaptic protein synthesis which is affected early in cognitive diseases. This data submission just includes mouse data.
2023-01-31 | GSE198526 | GEO
Project description:Stefan2008 - calmodulin allostery
An allosteric model for calmodulin activation, in which binding to calcium facilitates the transition between a low-affinity [tense (T)] and a high-affinity [relaxed (R)] state.
This model is described in the article:
An allosteric model of calmodulin explains differential activation of PP2B and CaMKII.
Stefan MI, Edelstein SJ, Le Novère N
Proc. Natl. Acad. Sci. U.S.A. 2008 Aug; 105(31): 10768-10773
Abstract:
Calmodulin plays a vital role in mediating bidirectional synaptic plasticity by activating either calcium/calmodulin-dependent protein kinase II (CaMKII) or protein phosphatase 2B (PP2B) at different calcium concentrations. We propose an allosteric model for calmodulin activation, in which binding to calcium facilitates the transition between a low-affinity [tense (T)] and a high-affinity [relaxed (R)] state. The four calcium-binding sites are assumed to be nonidentical. The model is consistent with previously reported experimental data for calcium binding to calmodulin. It also accounts for known properties of calmodulin that have been difficult to model so far, including the activity of nonsaturated forms of calmodulin (we predict the existence of open conformations in the absence of calcium), an increase in calcium affinity once calmodulin is bound to a target, and the differential activation of CaMKII and PP2B depending on calcium concentration.
This model is hosted on BioModels Database and identified by: BIOMD0000000183.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.
2008-07-15 | BIOMD0000000183 | BioModels
Project description:We previously found that mice with heterozygous knockout of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII HKO mice) show various dysregulated behaviors, including cyclic variations in locomotor activity (LA), suggesting that alpha-CaMKII HKO mice may serve as an animal model showing infradian oscillation of mood. We performed gene expression microarray analysis of dentate gyrus from alpha-CaMKII HKO mice. Mice were selected for the sampling such that their LA levels varied among the mice. Dentate gyrus RNA isolated from alpha-CaMKII HKO mice.
2016-03-29 | E-GEOD-68293 | biostudies-arrayexpress
Project description:We previously found that mice with heterozygous knockout of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII HKO mice) show various dysregulated behaviors, including cyclic variations in locomotor activity (LA), suggesting that alpha-CaMKII HKO mice may serve as an animal model showing infradian oscillation of mood. We performed gene expression microarray analysis of dentate gyrus from alpha-CaMKII HKO mice. Mice were selected for the sampling such that their LA levels varied among the mice.
2016-03-29 | GSE68293 | GEO
Project description:Regulator of G Protein Signaling 14 (RGS14) is a complex scaffolding protein with an unusual domain structure that allows it to integrate G protein and mitogen-activated protein kinase (MAPK) signaling pathways. RGS14 mRNA and protein are enriched in brain tissue of rodents and primates. In the adult mouse brain, RGS14 is predominantly expressed in postsynaptic dendrites and spines of hippocampal CA2 pyramidal neurons where it naturally inhibits synaptic plasticity and hippocampus-dependent learning and memory. However, the signaling proteins that RGS14 natively interacts with in neurons to regulate plasticity are unknown. Here, we show that RGS14 exists as a component of a high molecular weight protein complex in brain. To identify RGS14 neuronal interacting partners, endogenous RGS14 isolated from mouse brain was subjected to mass spectrometry and proteomic analysis. We find that RGS14 interacts with key postsynaptic proteins that regulate neuronal plasticity. Gene ontology analysis reveals that the most enriched RGS14 interacting proteins have functional roles in actin-binding, calmodulin(CaM)-binding, and CaM-dependent protein kinase (CaMK) activity. We validate these proteomics findings using biochemical assays that identify interactions between RGS14 and two previously unknown binding partners: CaM and CaMKII. We report that RGS14 directly interacts with CaM in a calcium-dependent manner and is phosphorylated by CaMKII in vitro. Lastly, we detect that RGS14 associates with CaMKII and with CaM in hippocampal CA2 neurons by proximity ligation assays in mouse brain sections. Taken together, these findings demonstrate that RGS14 is a novel CaM effector and CaMKII phosphorylation substrate thereby providing new insight into cellular mechanisms by which RGS14 controls plasticity in CA2 neurons.
2019-06-25 | PXD008461 | Pride
Project description:Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABAARs). BZ clinical use is hampered by tolerance and withdrawal symptoms, which include heightened seizure susceptibility, panic, and sleep disturbances. Here, we undergo a comprehensive investigation of inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Using quantitative proteomics approaches, we reveal cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways, highlighted by Ca2+/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling.
2023-10-24 | PXD041332 | Pride
Project description:The Ca2+/calmodulin-dependent kinase II is expressed in smooth muscle and believed to mediate intracellular calcium handling and calcium-dependent gene transcription. CaMKII is activated by Angiotensin-II. The multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by Angiotensin-II (Ang-II) in vascular smooth muscle cells (VSMC), but its impact on hypertension remains unknown. In our transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), the blood pressure response to chronic Ang-II infusion was significantly reduced as compared to littermate controls. Surprisingly, examination of blood pressure and heart rate under ganglionic blockade revealed a key role for VSMC CaMKII in efferent sympathetic outflow in response to Ang II hypertension. Consistently, the efferent splanchnic nerve activity and plasma phenylephrine concentrations were significantly lower in TG SM-CaMKIIN mice as compared to littermates. Moreover, the aortic depressor nerve activity was reset in hypertensive wild type animals, but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor wall activity may be responsible for the blood pressure difference in Ang-II hypertension. The pulse wave velocity, a measure of vascular wall stiffness in vivo, was increased in aortas of hypertensive compared to normotensive WT animals. However, Ang-II infusion did not alter the pulse wave velocity in transgenic mice, suggesting that CaMKII in VSMC controls structural smooth muscle genes. Accordingly, analysis of gene expression changes in aortas from wild type and TG SM-CaMKIIN hypertensive mice demonstrated that CaMKII inhibition mainly altered the expression of muscle contractile proteins. In contrast, TG SM-CaMKIIN aortas were protected from the Ang-II induced upregulation of genes linked to proliferation, suggesting that CaMKII inhibition prevents the Ang-II-induced reprogramming of smooth muscle cell gene expression towards a proliferative phenotype. 5 WT C57Bl/6 and 5 mice that express the Ca2+/calmodulin-dependent kinase II peptide inhibitor CaMKIIN in smooth muscle only (TG SM-CaMKIIN) were infused with 1.25 ug/kg/min Angiotensin-II by osmotic minipump for 14 days. 5 WT and 5 transgenic mice infused with normal saline served as controls. The mice were sacrificed on day 14 and the thoracic aortas isolated. RNA was isolated and pooled for the following groups: WT (wild type), C (TG SM-CaMKIIN), WT-A (WT with Angiotensin-II), C-A (TG SM-CaMKIIN + Angiotensin-II)
2015-07-01 | E-GEOD-64613 | biostudies-arrayexpress
Project description:The Ca2+/calmodulin-dependent kinase II is expressed in smooth muscle and believed to mediate intracellular calcium handling and calcium-dependent gene transcription. CaMKII is activated by Angiotensin-II. The multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by Angiotensin-II (Ang-II) in vascular smooth muscle cells (VSMC), but its impact on hypertension remains unknown. In our transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), the blood pressure response to chronic Ang-II infusion was significantly reduced as compared to littermate controls. Surprisingly, examination of blood pressure and heart rate under ganglionic blockade revealed a key role for VSMC CaMKII in efferent sympathetic outflow in response to Ang II hypertension. Consistently, the efferent splanchnic nerve activity and plasma phenylephrine concentrations were significantly lower in TG SM-CaMKIIN mice as compared to littermates. Moreover, the aortic depressor nerve activity was reset in hypertensive wild type animals, but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor wall activity may be responsible for the blood pressure difference in Ang-II hypertension. The pulse wave velocity, a measure of vascular wall stiffness in vivo, was increased in aortas of hypertensive compared to normotensive WT animals. However, Ang-II infusion did not alter the pulse wave velocity in transgenic mice, suggesting that CaMKII in VSMC controls structural smooth muscle genes. Accordingly, analysis of gene expression changes in aortas from wild type and TG SM-CaMKIIN hypertensive mice demonstrated that CaMKII inhibition mainly altered the expression of muscle contractile proteins. In contrast, TG SM-CaMKIIN aortas were protected from the Ang-II induced upregulation of genes linked to proliferation, suggesting that CaMKII inhibition prevents the Ang-II-induced reprogramming of smooth muscle cell gene expression towards a proliferative phenotype.
2015-07-01 | GSE64613 | GEO
Project description:This is an SBML version of the model described in: A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity.
Nakano T, Doi T, Yoshimoto J, Doya K. PLoS Comput Biol. 2010 Feb 12;6(2):e1000670. PMID: 20169176
; DOI: 10.1371/journal.pcbi.1000670
Abstract:
Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.
The model was encoded from the supplemental material accompanying the article.
The stimuli used in the article are hard to implement in SBML, so right now the model does not reproduce the results given in the article. Originally created by libAntimony v1.4 (using libSBML 3.4.1)This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1101170000 | BioModels