Dataset Information

Pepke2010_Full_Ca2/CaM_mCaMKII

ABSTRACT: This the full model from the article: A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II. Pepke S, Kinzer-Ursem T, Mihalas S, Kennedy MB. PLoS Comput Biol 2010 Feb 12;6(2):e1000675. PMID: 20168991 , doi: 10.1371/journal.pcbi.1000675 ; Abstract: During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning. The nomenclature of the different Calmodulin forms in th emodel differs from the description in the article. The C and N terminal Ca 2+ binding sites are described by the numbers at each species name, with the first entry indicating the number of Ca 2+ ions bound to the C and the second the ones bound on the N terminal sites. In complexes with two CaM, the four numbers at the end indicate _C_N_C_N. For example: CaM1N2C in the article is CaM_2_1 in the model, CaM4 is CaM_2_2 and KCaMcomplex_0_1_1_2 stands for CaMKII bound to CaM1C and CaM2N1C . This is a Systems Biology Markup Language (SBML) file, originally generated by MathSBML 2.9.0 [8-Oct-2008] 15-Jan-2010 13:13:32 (GMT-07:60). SBML is a form of XML, and most XML files will not display properly in an internet browser. To view the contents of an XML file use the "Page Source" or equivalent button on you browser. 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.

SUBMITTER: Tamara Kinzer-Ursem

PROVIDER: MODEL1001150000 | BioModels | 2005-01-01

REPOSITORIES: BioModels

ACCESS DATA

Publications

A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II.

Pepke Shirley S Kinzer-Ursem Tamara T Mihalas Stefan S Kennedy Mary B MB

PLoS computational biology 20100212 2

During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,inc ...[more]

PMID: 20168991

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.

Project description:MLC1 is membrane protein highly expressed by brain perivascular astrocytes. Mutations in MLC1 account for megalencephalic leukoencephalopathy with subcortical cysts (MLC), an incurable leu-kodystrophy characterized by macrocephaly, brain edema and cysts, myelin vacuolation and as-trocyte swelling, that cause cognitive and motor dysfunctions. MLC pathological models demon-strated that in astrocytes MLC1 mutations affect the swelling-activated Cl- currents (ICl,swell) medi-ated by volume-regulated anion channel (VRAC) and the consequent regulatory volume decrease (RVD), and also induce the abnormal activation of intracellular signaling pathways linked to in-flammation/osmotic stress. Despite this knowledge, MLC1 function and MLC molecular pathogen-esis are still elusive. Following the observations that calcium regulates all the MLC1-modulated processes and that intracellular Ca2+ homeostasis is altered in MLC1-defective cells, we applied biochemistry, molecular biology, video imaging, electrophysiology and proteomic techniques on cultured human and mouse astrocytes to study MLC1/calcium signaling relationships. We revealed that MLC1 binds the Ca2+ effector proteins calmodulin (CaM) and Ca2+/CaM-dependent protein ki-nase II (CaMKII) and, as result, changes its assembly, localization and functional properties in re-sponse to Ca2+ influx or release. Noteworthy, CaM binding to the COOH terminal promotes MLC1 trafficking to the plasma membrane, while CaMKII phosphorylation of the NH2 end potentiates MLC1 activation of ICl,swell, that are critically important for RVD. Overall, our results show that MLC1 is a Ca2+-regulated protein linking VRAC function and volume regulation to Ca2+ signaling in astro-cytes, opening new avenues to clarify the defective molecular pathways of MLC and other diseas-es where astrocyte swelling and brain edema underlie the pathological process. In this contest we submit here the MS data showing MLC phosphorylation on Threonine 17.

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)

Dataset Information

Pepke2010_Full_Ca2/CaM_mCaMKII

Publications

A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure