Ca-CaM-AMPK signaling models - Revision history

Akberdinir@gmail.com: /* Ca-CaM-AMPK signaling pathway */

2021-03-06T11:03:48Z

‎Ca-CaM-AMPK signaling pathway

Akberdinir@gmail.com: /* Published models */

2021-03-06T10:54:01Z

‎Published models

Akberdinir@gmail.com at 07:06, 17 July 2019

2019-07-17T07:06:35Z

Akberdinir@gmail.com at 06:27, 26 March 2019

2019-03-26T06:27:12Z

Akberdinir@gmail.com at 06:20, 26 March 2019

2019-03-26T06:20:43Z

Akberdinir@gmail.com at 06:15, 26 March 2019

2019-03-26T06:15:43Z

Akberdinir@gmail.com at 11:12, 25 March 2019

2019-03-25T11:12:09Z

Akberdinir@gmail.com at 10:26, 25 March 2019

2019-03-25T10:26:58Z

Akberdinir@gmail.com at 10:03, 25 March 2019

2019-03-25T10:03:29Z

Akberdinir@gmail.com at 10:20, 25 February 2019

2019-02-25T10:20:10Z

← Older revision		Revision as of 11:03, 6 March 2021
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	<span style="font-size: 90%"> '''Figure 2''' Schematic diagramme of Ca-CaM-AMPK signaling pathway designed in SBGN standard using BioUML tool. All abbreviations for objects in the main text.</span>		<span style="font-size: 90%"> '''Figure 2''' Schematic diagramme of Ca-CaM-AMPK signaling pathway designed in SBGN standard using BioUML tool. All abbreviations for objects in the main text.</span>
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	===Published models===		===Published models===

← Older revision		Revision as of 10:54, 6 March 2021
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	<span style="font-size: 90%"> '''Figure 9 from (Eilers et al., 2012)''' <cite>30</cite> A/C: Total CaMKII activity (the sum of P<sub>b</sub>, P<sub>t</sub>, P<sub>t2</sub> and P<sub>a</sub> - see Fig. 4) during a simulation of a single RyR opening in the fast-twitch (FT; A) and slow-twitch (ST; C) model in which CaMKII concentration is increased. Lines indicate CaMKII activity in different myoplasmic compartments. Blue lines: [CaMKII] = 1 µM; Red lines: [CaMKII] = 50 µM. Note that the scales on the y-axes are different; B/D: Spatially averaged [Ca<sup>2+</sup>] (left graphs) and [Ca<sup>2+</sup>-TropC] (right graphs) during a simulation of one RyR opening in the FT (B) and ST (D) model. Blue lines: [CaMKII] = 1 µM; Red lines: [CaMKII] = 50 µM. Note that scales on the y-axes are different.</span>		<span style="font-size: 90%"> '''Figure 9 from (Eilers et al., 2012)''' <cite>30</cite> A/C: Total CaMKII activity (the sum of P<sub>b</sub>, P<sub>t</sub>, P<sub>t2</sub> and P<sub>a</sub> - see Fig. 4) during a simulation of a single RyR opening in the fast-twitch (FT; A) and slow-twitch (ST; C) model in which CaMKII concentration is increased. Lines indicate CaMKII activity in different myoplasmic compartments. Blue lines: [CaMKII] = 1 µM; Red lines: [CaMKII] = 50 µM. Note that the scales on the y-axes are different; B/D: Spatially averaged [Ca<sup>2+</sup>] (left graphs) and [Ca<sup>2+</sup>-TropC] (right graphs) during a simulation of one RyR opening in the FT (B) and ST (D) model. Blue lines: [CaMKII] = 1 µM; Red lines: [CaMKII] = 50 µM. Note that scales on the y-axes are different.</span>
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	===References===		===References===

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 <p align=justify> Ca<sup>2+</sup> influx into mitochondria has been shown to result in increased energy conversion potential which is necessary in the maintenance of energetic homeostasis in contracting muscle (Korzeniewski, 2007) <cite>6</cite>. Recent data support this notion of Ca<sup>2+</sup>-activated muscle oxidative phosphorylation cascade. It could be shown that Ca<sup>2+</sup> increased the conductance of complex IV, complexes I + III, ATP production/transport, and fuel transport/dehydrogenases (Glancy et al., 2013) <cite>7</cite>. Ca<sup>2+</sup> concentration has also been shown to directly stimulate ATP production through activation of the F1F0-ATP synthase at least in cardiac muscle (Territo et al., 2000) <cite>8</cite>. Extrapolation of these data to the exercising muscle predicts a significant role of Ca<sup>2+</sup> concentration in maintaining cellular energy homeostasis. The activation of the electron transport chain in mitochondria by Ca<sup>2+</sup> concentration may significantly contribute to the Ca<sup>2+</sup> stimulation of ATP production during exercise (Glancy et al., 2013) <cite>7</cite>.</p>
-<p align=justify> Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis, angiogenesis, as well as fat and carbohydrate metabolism in skeletal muscle (Olesen et al., 2010,  Popov et al., 2015) <cite>9</cite> <cite>10</cite>. Mouse and human skeletal muscle expresses several PGC-1α (PPARGC1A) gene isoforms originating from the canonical (PGC-1α-a mRNA) and alternative (PGC-1α-b and PGC-1α-c mRNA) promoters (Miura et al., 2008, Yoshioka et al., 2009) <cite>11</cite> <cite>12</cite>. Alternative splicing at the intron between exons 6 and 7 can generate N-truncated (NT) PGC-1α isoforms (Zhang et al., 2009) <cite>13</cite>, which possess unique properties, different to those of full-length isoforms (Thom et al., 2014) <cite>14</cite>. Thus, the PGC-1α gene has the potential to produce at least six transcripts (Chang et al., 2012) <cite>15</cite>. Acute endurance exercise leads to increased PGC-1α gene expression in skeletal muscle. AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), Ca<sup>2+</sup>/calmodulin-dependent protein kinase (CaMKII) and [http://virtualbiology.biouml.org/index.php/CaMKK%CE%B2 Ca2+/calmodulin-dependent protein kinase kinase β] (CaMKKII) appear to be important for regulation of activity-induced PGC-1α gene expression from the canonical promoter (Zhang et al., 2014) <cite>16</cite>. Several groups (Norrbom et al., 2011, Ydfors et al., 2013, Popov et al., 2014) <cite>17</cite> <cite>18</cite> <cite>19</cite> have shown that in human skeletal muscle, acute exercise induces PGC-1α gene expression, mainly via the alternative promoter. Based on studies in rodent skeletal muscle, it was proposed that activation of exercise-induced expression via the alternative promoter is regulated by the beta-2 adrenergic receptor-protein kinase A (PKA)-cAMP response element-binding protein (CREB1) signalling pathway (Chinsomboon et al., 2009, Tadaishi et al., 2011) <cite>20</cite> <cite>21</cite>. Human myoblast (Norrbom et al., 2011) <cite>17</cite> and mouse (Wen et al., 2014) <cite>22</cite> studies showed that AMPK plays a role in the regulation of expression via the alternative promoter. However, another myoblast study (Yoshioka et al., 2009) <cite>12</cite> and a study in isolated rat muscle (Tadaishi et al., 2011) <cite>21</cite> did not confirm this finding. Furthermore, it has been demonstrated that constitutive expression PGC-1α gene occurs via the canonical promoter, independent of exercise intensity and exercise-induced increase of AMPK<sup>Thr172</sup> phosphorylation level. Expression of PGC-1α gene via the alternative promoter is increased of two orders after exercise. This post-exercise expression is highly dependent on the intensity of exercise. There is an apparent association between expression via the alternative promoter and activation of CREB1 (Popov et al., 2015) <cite>23</cite> (Figure 2).</p>
+<p align=justify> Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis, angiogenesis, as well as fat and carbohydrate metabolism in skeletal muscle (Olesen et al., 2010,  Popov et al., 2015) <cite>9</cite> <cite>10</cite>. Mouse and human skeletal muscle expresses several PGC-1α (PPARGC1A) gene isoforms originating from the canonical (PGC-1α-a mRNA) and alternative (PGC-1α-b and PGC-1α-c mRNA) promoters (Miura et al., 2008, Yoshioka et al., 2009) <cite>11</cite> <cite>12</cite>. Alternative splicing at the intron between exons 6 and 7 can generate N-truncated (NT) PGC-1α isoforms (Zhang et al., 2009) <cite>13</cite>, which possess unique properties, different to those of full-length isoforms (Thom et al., 2014) <cite>14</cite>. Thus, the PGC-1α gene has the potential to produce at least six transcripts (Chang et al., 2012) <cite>15</cite>. Acute endurance exercise leads to increased PGC-1α gene expression in skeletal muscle. [http://virtualbiology.biouml.org/index.php/AMPK AMP-activated protein kinase (AMPK)], p38 mitogen-activated protein kinase (p38 MAPK), Ca<sup>2+</sup>/calmodulin-dependent protein kinase (CaMKII) and [http://virtualbiology.biouml.org/index.php/CaMKK%CE%B2 Ca2+/calmodulin-dependent protein kinase kinase β] (CaMKKII) appear to be important for regulation of activity-induced PGC-1α gene expression from the canonical promoter (Zhang et al., 2014) <cite>16</cite>. Several groups (Norrbom et al., 2011, Ydfors et al., 2013, Popov et al., 2014) <cite>17</cite> <cite>18</cite> <cite>19</cite> have shown that in human skeletal muscle, acute exercise induces PGC-1α gene expression, mainly via the alternative promoter. Based on studies in rodent skeletal muscle, it was proposed that activation of exercise-induced expression via the alternative promoter is regulated by the beta-2 adrenergic receptor-protein kinase A (PKA)-cAMP response element-binding protein (CREB1) signalling pathway (Chinsomboon et al., 2009, Tadaishi et al., 2011) <cite>20</cite> <cite>21</cite>. Human myoblast (Norrbom et al., 2011) <cite>17</cite> and mouse (Wen et al., 2014) <cite>22</cite> studies showed that AMPK plays a role in the regulation of expression via the alternative promoter. However, another myoblast study (Yoshioka et al., 2009) <cite>12</cite> and a study in isolated rat muscle (Tadaishi et al., 2011) <cite>21</cite> did not confirm this finding. Furthermore, it has been demonstrated that constitutive expression PGC-1α gene occurs via the canonical promoter, independent of exercise intensity and exercise-induced increase of AMPK<sup>Thr172</sup> phosphorylation level. Expression of PGC-1α gene via the alternative promoter is increased of two orders after exercise. This post-exercise expression is highly dependent on the intensity of exercise. There is an apparent association between expression via the alternative promoter and activation of CREB1 (Popov et al., 2015) <cite>23</cite> (Figure 2).</p>
 [[File:Ca-CaM-AMPK_pathway_02_15_2019.png|center]]

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-|<gallery mode="packed" heights="600px">
+|<gallery mode="packed" heights="500px">
    Eilers_etal_2012_Fig7.png|<br><span style="font-size: 90%; align="right"">'''Figure 7 from (Eilers et al., 2012)''' <cite>30</cite>. CaMKII activity during a single RyR opening. Total simulated CaMKII activity (the sum of P<sub>b4</sub>, P<sub>t2</sub>, P<sub>t4</sub> and P<sub>a</sub> - see Fig. 4) during a simulated single RyR opening in the fast-twitch (FT) and slow-twitch (ST) model (see text for model details). Graphs on the left display development of total CaMKII activity over time (in milliseconds) during a single RyR opening in the FT and ST model as indicated. Blue lines represent CaMKII activity in different myoplasmic compartments. Black inverted triangles indicate the approximate time point at which the CaMKII activity gradient was analysed, and visualised in the grids on the right. Note that the scale of the y-axis differs in the FT and ST graph. Grids on the right visualise the spatial distribution of the maximal increase in total CaMKII activity during a single simulated RyR opening. Colours indicate the percentage increase compared to the initial total activity, and the scale is indicated above the figure. Grid layout is the same as in Fig. 5A. The locations of the z-line and m-line of the half-sarcomeric model are indicated by Z and M, respectively. NSR: nonjunctional sarcoplasmic reticulum. JSR: junctional sarcoplasmic reticulum. SERCA: sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase. RyR: Ryanodine receptor.</span>
-   Eilers_etal_2012_Fig8.png|<br><span style="font-size: 90%; align="right"">'''Figure 8 from (Eilers et al., 2012)''' <cite>30</cite>. CaMKII activity during repeated RyR openings. Total simulated CaMKII activity (the sum of P<sub>b4</sub>, P<sub>t2</sub>, P<sub>t4</sub> and P<sub>a</sub> - see Fig. 4) during a simulation of ten RyR openings in the fast-twitch (FT) and slow-twitch (ST) model. Graphs on the left display development of total CaMKII activity over time (in milliseconds) during ten simulated RyR openings in FT and ST model as indicated, and at a RyR opening frequency of 100Hz (upper two graphs) or 10Hz (lower two graphs). Blue lines represent CaMKII activity in different myoplasmic compartments. In order to optimise visualisation of the graphs, the scale of the y-axis differs in each graph. Grids on the right visualise the spatial distribution of maximal total CaMKII activation during the simulation of ten RyR openings. Colours indicate the percentage increase compared to the initial total activity, and the scale is indicated above the figure. Note that colour scale in this figure is of larger magnitude compared to Fig. 7. Grid layout is the same as in Fig. 5A.</span>
+   Eilers_etal_2012_Fig8_edit.png|<br><span style="font-size: 90%; align="right"">'''Figure 8 from (Eilers et al., 2012)''' <cite>30</cite>. CaMKII activity during repeated RyR openings. Total simulated CaMKII activity (the sum of P<sub>b4</sub>, P<sub>t2</sub>, P<sub>t4</sub> and P<sub>a</sub> - see Fig. 4) during a simulation of ten RyR openings in the fast-twitch (FT) and slow-twitch (ST) model. Graphs on the left display development of total CaMKII activity over time (in milliseconds) during ten simulated RyR openings in FT and ST model as indicated, and at a RyR opening frequency of 100Hz (upper two graphs) or 10Hz (lower two graphs). Blue lines represent CaMKII activity in different myoplasmic compartments. In order to optimise visualisation of the graphs, the scale of the y-axis differs in each graph. Grids on the right visualise the spatial distribution of maximal total CaMKII activation during the simulation of ten RyR openings. Colours indicate the percentage increase compared to the initial total activity, and the scale is indicated above the figure. Note that colour scale in this figure is of larger magnitude compared to Fig. 7. Grid layout is the same as in Fig. 5A.</span>
 </gallery>
 |}

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 {| align="center" style="background:#f8f9fa; border:1px solid #c8ccd1; font-size:100%; margin-center:1em" cellspacing=0 cellpadding=0
 |-
-|<gallery mode="packed" heights="300px">
+|<gallery mode="packed" heights="600px">
-   Eilers_etal_2012_Fig7.png|<br><span style="font-size: 90%; align="right"">'''Figure 7 from (Eilers et al., 2012)''' <cite>30</cite>. CaMKII activity during a single RyR opening. Total simulated CaMKII activity (the sum of P<sub>b4</sub>, P<sub>t2</sub>, P<sub>t4</sub> and P<sub>a</sub> - see Fig. 4) during a simulated single RyR opening in the fast-twitch (FT) and slow-twitch (ST) model (see text for model details). Graphs on the left display development of total CaMKII activity over time (in milliseconds) during a single RyR opening in the FT and ST model as indicated. Blue lines represent CaMKII activity in different myoplasmic compartments. Black inverted triangles indicate the approximate time point at which the CaMKII activity gradient was analysed, and visualised in the grids on the right. Note that the scale of the y-axis differs in the FT and ST graph. Grids on the right visualise the spatial distribution of the maximal increase in total CaMKII activity during a single simulated RyR opening. Colours indicate the percentage increase compared to the initial total activity, and the scale is indicated above the figure. Grid layout is the same as in Fig. 5A. The locations of the zline and m-line of the half-sarcomeric model are indicated by Z and M, respectively. NSR: nonjunctional sarcoplasmic reticulum. JSR: junctional sarcoplasmic reticulum. SERCA: sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase. RyR: Ryanodine receptor.</span>
+   Eilers_etal_2012_Fig7.png|<br><span style="font-size: 90%; align="right"">'''Figure 7 from (Eilers et al., 2012)''' <cite>30</cite>. CaMKII activity during a single RyR opening. Total simulated CaMKII activity (the sum of P<sub>b4</sub>, P<sub>t2</sub>, P<sub>t4</sub> and P<sub>a</sub> - see Fig. 4) during a simulated single RyR opening in the fast-twitch (FT) and slow-twitch (ST) model (see text for model details). Graphs on the left display development of total CaMKII activity over time (in milliseconds) during a single RyR opening in the FT and ST model as indicated. Blue lines represent CaMKII activity in different myoplasmic compartments. Black inverted triangles indicate the approximate time point at which the CaMKII activity gradient was analysed, and visualised in the grids on the right. Note that the scale of the y-axis differs in the FT and ST graph. Grids on the right visualise the spatial distribution of the maximal increase in total CaMKII activity during a single simulated RyR opening. Colours indicate the percentage increase compared to the initial total activity, and the scale is indicated above the figure. Grid layout is the same as in Fig. 5A. The locations of the z-line and m-line of the half-sarcomeric model are indicated by Z and M, respectively. NSR: nonjunctional sarcoplasmic reticulum. JSR: junctional sarcoplasmic reticulum. SERCA: sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase. RyR: Ryanodine receptor.</span>
-   Eilers_etal_2012_Fig8.png|<br><span style="font-size: 90%; align="right"">'''Figure 8 from (Eilers et al., 2012)''' <cite>30</cite>. CaMKII activity during repeated RyR openings. Total simulated CaMKII activity (the sum of P<sub>b4</sub>, P<sub>t2</sub>, P<sub>t4</sub> and P<sub>a</sub> - see Fig. 4) during a simulation of ten RyR openings in the fast-twitch (FT) and slow-twitch (ST) model (see text for model details). Graphs on the left display development of total CaMKII activity over time (in milliseconds) during ten simulated RyR openings in FT and ST model as indicated, and at a RyR opening frequency of 100Hz (upper two graphs) or 10Hz (lower two graphs). Blue lines represent CaMKII activity in different myoplasmic compartments. In order to optimise visualisation of the graphs, the scale of the y-axis differs in each graph. Black inverted triangles indicate the approximate time point at which the CaMKII activity gradient was analysed, and visualised in the grids on the right. Grids on the right visualise the spatial distribution of maximal total CaMKII activation during the simulation of ten RyR openings. Colours indicate the percentage increase compared to the initial total activity, and the scale is indicated above the figure. Note that colour scale in this figure is of larger magnitude compared to Fig. 7. Grid layout is the same as in Fig. 5A. The locations of the zline and m-line of the half-sarcomeric model are indicated by Z and M, respectively. NSR: nonjunctional sarcoplasmic reticulum. JSR: junctional sarcoplasmic reticulum. SERCA: sarco/endoplasmic reticulum Ca2+-ATPase. RyR: Ryanodine receptor.</span>
+   Eilers_etal_2012_Fig8.png|<br><span style="font-size: 90%; align="right"">'''Figure 8 from (Eilers et al., 2012)''' <cite>30</cite>. CaMKII activity during repeated RyR openings. Total simulated CaMKII activity (the sum of P<sub>b4</sub>, P<sub>t2</sub>, P<sub>t4</sub> and P<sub>a</sub> - see Fig. 4) during a simulation of ten RyR openings in the fast-twitch (FT) and slow-twitch (ST) model. Graphs on the left display development of total CaMKII activity over time (in milliseconds) during ten simulated RyR openings in FT and ST model as indicated, and at a RyR opening frequency of 100Hz (upper two graphs) or 10Hz (lower two graphs). Blue lines represent CaMKII activity in different myoplasmic compartments. In order to optimise visualisation of the graphs, the scale of the y-axis differs in each graph. Grids on the right visualise the spatial distribution of maximal total CaMKII activation during the simulation of ten RyR openings. Colours indicate the percentage increase compared to the initial total activity, and the scale is indicated above the figure. Note that colour scale in this figure is of larger magnitude compared to Fig. 7. Grid layout is the same as in Fig. 5A.</span>
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 <p align=justify> This detailed biochemical model describing CaMKII activation (Saucerman and Bers, 2008) <cite>28</cite> was extended with a computational model describing spatiotemporal [Ca<sup>2+</sup>] dynamics in a half sarcomere of a fast-twitch mouse muscle (Groenendaal et al., 2008) <cite>29</cite> by group of Prof. Martin Flueck from the Institute for Biomedical Research into Human Movement and Health of Manchester Metropolitan University (Eilers et al., 2012, 2014) <cite>30</cite>,<cite>31</cite>. Both models <cite>28</cite>,<cite>29</cite> consist of coupled differential equations and contain no stochastic elements. The sarcomeric model describes a cylinder consisting of four radial layers, of which the inner three form the myoplasm and the outer layer forms the sarcoplasmic reticulum (SR). Longitudinally, the layers are divided into six parts of equal volume, to form 18 myoplasmic elements and six SR elements (Fig. 5A). The number of elements in the model was limited to 24 to prevent excessive computational times and remain within computer memory limits. The elements include buffering of calcium by troponin-C, parvalbumin (in fast-twitch muscle) and ATP in the myoplasm and calsequestrin in the SR. In the model, calcium is able to diffuse within the myoplasm and the SR, and is transported between these two compartments through the RyR and SERCA, which have distinct locations on the modelled SR (Fig. 5A). To each myoplasmic element in the model <cite>30</cite>, authors added a CaMKII reaction scheme describing Ca<sup>2+</sup> binding to calmodulin (CaM) (Fig. 5B) and subsequent binding of Ca<sup>2+</sup>-CaM to CaMKII (Saucerman and Bers, 2008) <cite>28</cite>. Unlike the previous model <cite>28</cite>,  CaM-buffering was removed from the model and only free CaM was considered.</p>
-[[File:Saucerman_and_Bers_2008.jpg|center]]
+[[File:Eilers_etal_2012_Fig5.png|center]]
 <span style="font-size: 90%"> '''Figure 5 from (Eilers et al., 2012)''' <cite>30</cite> Schematized calcium model and CaM-CaMKII reaction schemes. (A) Simplified visualisation of the different spatial elements in the computational model of calcium dynamics in a half-sarcomere, adapted from Groenendaal et al., 2008 <cite>29</cite>. The model is bordered by a z-line on one side and an m-line on the other side. The grey elements (top row) make up the SR and the white elements (bottom tree rows) make up the myoplasm. Note that the actual model is a cylinder, and the elements are actually rings, with the lower border of the bottom elements as their centre; (B) Reaction scheme for sequential binding of calcium to the C-terminal and then the N-terminal EF-hand of calmodulin.</span>
-<p align=justify> To validate the CaMKII reaction scheme, we first compared modelled Ca<sup>2+</sup>-sensitivity of CaMKII autophosphorylation and the effect of phosphatase concentration on this relationship to that of an independent experimental dataset (Bradshaw et al., 2003) <cite>32</cite>. The model reproduced the concentration for half-maximal activation and steepness of the relationship between [Ca<sup>2+</sup>] and CaMKII autophosphorylation quite well (Fig. 6A). Furthermore, we compared the modelled relation between [CaM] and CaMKII activity, and between [CaM] and CaMKII autophosphorylation, with another independent experimental dataset (Gaertner et al., 2004) <cite>33</cite>. The model properly described the experimentally determined [Ca<sup>2+</sup>] concentrations for half-maximal CaMKII activity and the steepness of the curve (Fig. 6B&C).</p>
+<p align=justify> To validate the CaMKII reaction scheme, Eilers and coauthors first compared modelled Ca<sup>2+</sup>-sensitivity of CaMKII autophosphorylation and the effect of phosphatase concentration on this relationship to that of an independent experimental dataset (Bradshaw et al., 2003) <cite>32</cite>. The model reproduced the concentration for half-maximal activation and steepness of the relationship between [Ca<sup>2+</sup>] and CaMKII autophosphorylation quite well (Fig. 6A). Furthermore, authors compared the modelled relation between [CaM] and CaMKII activity, and between [CaM] and CaMKII autophosphorylation, with another independent experimental dataset (Gaertner et al., 2004) <cite>33</cite>. The model properly described the experimentally determined [Ca<sup>2+</sup>] concentrations for half-maximal CaMKII activity and the steepness of the curve (Fig. 6B&C).</p>
-[[File:Saucerman_and_Bers_2008.jpg|center]]
+[[File:Eilers_etal_2012_Fig6.png|center]]
-<span style="font-size: 90%"> '''Figure 6 from (Eilers et al., 2012)''' <cite>30</cite> Validation of CaM-CaMKII reaction scheme. (A) Comparison of modelled [Ca<sup>2+</sup>] - phospho<sup>Thr287</sup>-CaMKII relation (blue lines) with published data (red open circles: 0.5 μM PP1; green circles: 2.5 μM PP1) (Bradshaw et al., 2003) <cite>32</cite>; (B) Comparison of modelled [CaM] - CaMKII activity relation (blue line) with independent experimental data (Gaertner et al., 2004) <cite>33</cite>; (C) Comparison of modelled [CaM] - CaMKII autophosphorylation relation (blue lines) with independent experimental data (Gaertner et al.,
+<span style="font-size: 90%"> '''Figure 6 from (Eilers et al., 2012)''' <cite>30</cite> Validation of CaM-CaMKII reaction scheme. (A) Comparison of modelled [Ca<sup>2+</sup>] - phospho<sup>Thr287</sup>-CaMKII relation (blue lines) with published data (red open circles: 0.5 μM PP1; green circles: 2.5 μM PP1) (Bradshaw et al., 2003) <cite>32</cite>; (B) Comparison of modelled [CaM] - CaMKII activity relation (blue line) with independent experimental data (Gaertner et al., 2004) <cite>33</cite>; (C) Comparison of modelled [CaM] - CaMKII autophosphorylation relation (blue lines) with independent experimental data (Gaertner et al., 2004) <cite>33</cite>. Experimental data points are estimated from graphs in cited papers. PP1: Protein phosphatase 1.</span>
-<p align=justify> The model simulations of CaMKII activity in skeletal muscle sarcomeres and its effects demonstrate CaMKII is locally activated, and its spatial activity gradient is maintained during repeated stimulation. Therefore, the location of CaMKII in a sarcomere is likely to be of importance for its function and should be considered when evaluating potential CaMKII targets for physiological relevance.</p>
+<p align=justify> Eilers et al found that the modelled spatial gradient in cytoplasmic [Ca<sup>2+</sup>] results in a two-fold decrease in CaMKII activity between the Ca<sup>2+</sup> release site (i.e. near the z-line) and the part of the sarcomere close to the m-line. This gradient existed during simulations of a single RyR opening and simulations of repeated trains of RyR opening (Fig. 3, 4 & 5). Furthermore, simulated

@@ Line 41: / Line 41: @@
-<p align=justify> This detailed biochemical model describing CaMKII activation (Saucerman and Bers, 2008) <cite>28</cite> was extended with a computational model describing spatiotemporal [Ca<sup>2+</sup>] dynamics in a half sarcomere of a fast-twitch mouse muscle (Groenendaal et al., 2008) <cite>29</cite> by group of Prof. Martin Flueck from the Institute for Biomedical Research into Human Movement and Health of Manchester Metropolitan University (Eilers et al., 2012, 2014) <cite>30</cite>,<cite>31</cite>. Both models <cite>28</cite>,<cite>29</cite> consist of coupled differential equations and contain no stochastic elements. The sarcomeric model describes a cylinder consisting of four radial layers, of which the inner three form the myoplasm and the outer layer forms the sarcoplasmic reticulum (SR). Longitudinally, the layers are divided into six parts of equal volume, to form 18 myoplasmic elements and six SR elements (Fig. 5A). The number of elements in the model was limited to 24 to prevent excessive computational times and remain within computer memory limits. The elements include buffering of calcium by troponin-C, parvalbumin (in fast-twitch muscle) and ATP in the myoplasm and calsequestrin in the SR. In the model, calcium is able to diffuse within the myoplasm and the SR, and is transported between these two compartments through the RyR and SERCA, which have distinct locations on the modelled SR (Fig. 5A). To each myoplasmic element in the model, they added a CaMKII reaction scheme
+<p align=justify> This detailed biochemical model describing CaMKII activation (Saucerman and Bers, 2008) <cite>28</cite> was extended with a computational model describing spatiotemporal [Ca<sup>2+</sup>] dynamics in a half sarcomere of a fast-twitch mouse muscle (Groenendaal et al., 2008) <cite>29</cite> by group of Prof. Martin Flueck from the Institute for Biomedical Research into Human Movement and Health of Manchester Metropolitan University (Eilers et al., 2012, 2014) <cite>30</cite>,<cite>31</cite>. Both models <cite>28</cite>,<cite>29</cite> consist of coupled differential equations and contain no stochastic elements. The sarcomeric model describes a cylinder consisting of four radial layers, of which the inner three form the myoplasm and the outer layer forms the sarcoplasmic reticulum (SR). Longitudinally, the layers are divided into six parts of equal volume, to form 18 myoplasmic elements and six SR elements (Fig. 5A). The number of elements in the model was limited to 24 to prevent excessive computational times and remain within computer memory limits. The elements include buffering of calcium by troponin-C, parvalbumin (in fast-twitch muscle) and ATP in the myoplasm and calsequestrin in the SR. In the model, calcium is able to diffuse within the myoplasm and the SR, and is transported between these two compartments through the RyR and SERCA, which have distinct locations on the modelled SR (Fig. 5A). To each myoplasmic element in the model <cite>30</cite>, authors added a CaMKII reaction scheme describing Ca<sup>2+</sup> binding to calmodulin (CaM) (Fig. 5B) and subsequent binding of Ca<sup>2+</sup>-CaM to CaMKII (Saucerman and Bers, 2008) <cite>28</cite>. Unlike the previous model <cite>28</cite>,  CaM-buffering was removed from the model and only free CaM was considered.</p>
-describing Ca<sup>2+</sup> binding to calmodulin (CaM) (Fig. 1B) and subsequent binding of Ca<sup>2+</sup>-CaM to CaMKII (Saucerman and Bers, 2008). Unlike the previous model <cite>28</cite>,  CaM-buffering was removed from the model and only free CaM was considered.</p>
@@ Line 78: / Line 92: @@
 #30 https://e-space.mmu.ac.uk/315671/1/SENSORY%20PATHWAYS%20OF%20MUSCLE%20PHENOTYPIC%20PLASTICITY_FINAL_DEC2012.pdf	<!--Eilers et al 2012 -->
 #31 pmid=25054156	<!-- Eilers et al 2014 -->

@@ Line 41: / Line 41: @@
-<p align=justify> This detailed biochemical model describing CaMKII activation (Saucerman and Bers, 2008) <cite>28</cite> was extended with a computational model describing spatiotemporal [Ca2+] dynamics in a half sarcomere of a fast-twitch mouse muscle (Groenendaal et al., 2008) <cite>29</cite> by group of Prof. Martin Flueck from the Institute for Biomedical Research into Human Movement and Health of Manchester Metropolitan University (Eilers et al., 2012, 2014) <cite>30-31</cite>. </p>
+<p align=justify> This detailed biochemical model describing CaMKII activation (Saucerman and Bers, 2008) <cite>28</cite> was extended with a computational model describing spatiotemporal [Ca<sup>2+</sup>] dynamics in a half sarcomere of a fast-twitch mouse muscle (Groenendaal et al., 2008) <cite>29</cite> by group of Prof. Martin Flueck from the Institute for Biomedical Research into Human Movement and Health of Manchester Metropolitan University (Eilers et al., 2012, 2014) <cite>30</cite>,<cite>31</cite>. Both models <cite>28</cite>,<cite>29</cite> consist of coupled differential equations and contain no stochastic elements. The sarcomeric model describes a cylinder consisting of four radial layers, of which the inner three form the myoplasm and the outer layer forms the sarcoplasmic reticulum (SR). Longitudinally, the layers are divided into six parts of equal volume, to form 18 myoplasmic elements and six SR elements (Fig. 5A). The number of elements in the model was limited to 24 to prevent excessive computational times and remain within computer memory limits. The elements include buffering of calcium by troponin-C, parvalbumin (in fast-twitch muscle) and ATP in the myoplasm and calsequestrin in the SR. In the model, calcium is able to diffuse within the myoplasm and the SR, and is transported between these two compartments through the RyR and SERCA, which have distinct locations on the modelled SR (Fig. 5A). To each myoplasmic element in the model, they added a CaMKII reaction scheme
@@ Line 75: / Line 76: @@
 #28 pmid=18689454	<!-- Saucerman and Bers 2008 -->
 #29 pmid=19045836	<!-- Groenendaal et al 2008 -->
-#30 https://link.springer.com/content/pdf/10.1007/978-3-540-69389-5_14.pdf	<!--Eilers et al 2012 -->
+#30 https://e-space.mmu.ac.uk/315671/1/SENSORY%20PATHWAYS%20OF%20MUSCLE%20PHENOTYPIC%20PLASTICITY_FINAL_DEC2012.pdf	<!--Eilers et al 2012 -->
 #31 pmid=25054156	<!-- Eilers et al 2014 -->

@@ Line 39: / Line 39: @@
 <span style="font-size: 90%"> '''Figure 4 from (Saucerman and Bers, 2008)''' <cite>28</cite> Model of calmodulin (CaM)-dependent signaling in cardiac myocytes. (A) Compartmental model schematic of cardiac myocyte EC coupling <cite>27</cite> incorporating CaM, CaMKII, and CaN signaling in thedyadic cleft and cytosol; (B) Reaction map for cooperative Ca binding of 2 Ca to CaM sequentially to the C-terminal and then N-terminal EF hands, along with binding of CaM “buffers”; (C) Probabilistic model of CaMKII''δ'' subunit switching between inactive (P<sub>i</sub>), inactive Ca<sub>2</sub>CaM-bound (P<sub>b2</sub>), active Ca<sub>4</sub>CaM-bound (P<sub>b</sub>), Thr<sup>287</sup>-autophosphorylated with Ca<sub>4</sub>CaM trapped (P<sub>t</sub>), and Thr<sup>287</sup>-autophosphorylated but CaM-autonomous (P<sub>a</sub>) or Ca<sub>2</sub>CaM-bound (P<sub>t2</sub>) states. (D) Reaction map for reversible binding of CaM, Ca<sub>2</sub>CaM, and Ca<sub>4</sub>CaM to CaN.</span>
@@ Line 71: / Line 74: @@
 #27 pmid=16169970	<!-- Shannon et al 2005 -->
 #28 pmid=18689454	<!-- Saucerman and Bers 2008 -->
 </biblio>

← Older revision		Revision as of 10:20, 25 February 2019
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	[[File:Cui_calcium_2008.png\|center]]		[[File:Cui_calcium_2008.png\|center]]

−	<span style="font-size: 90%"> '''Figure 3 from (Cui and Kaandorp, 2008)''' <cite>25</cite> A schematic graph depicting the ~~Ca2~~+-calcineurin-MCIP-NFAT signaling networks in cardiac myocytes (for details, please see the main text). Abbreviations are as follows: calmodulin (CaM); calcineurin (CaN); activated calcineurin (CaN∗); nuclear factor of activated T-cells (NFAT); phosphrylated NFAT(NFAT<sup>p</sup>); modulatory calcineurin-interacting protein (MCIP); phosphorylated MCIP on serine 112 (MCIP<sup>p</sup>); phosphorylated MCIP on both serine 112 and serine 108 (MCIP<sup>pp</sup>); big mitogenactivated protein kinase 1 (BMK1); glycogen synthase 3''β'' (GSK3''β''); the complex formed by MCIP and calcineurin (Complex1); the complex formed by MCIP<sup>pp</sup> and protein 14-3-3 (Complex2); the complex formed by NFAT<sup>p</sup> and protein 14-3-3 (Complex3); pressure overload (PO); hypertrophic stimuli (stress). The stress of PO is delivered by transverse aortic constriction (TAC).</span>	+	<span style="font-size: 90%"> '''Figure 3 from (Cui and Kaandorp, 2008)''' <cite>25</cite> A schematic graph depicting the Ca<sup>2+</sup>-calcineurin-MCIP-NFAT signaling networks in cardiac myocytes (for details, please see the main text). Abbreviations are as follows: calmodulin (CaM); calcineurin (CaN); activated calcineurin (CaN∗); nuclear factor of activated T-cells (NFAT); phosphrylated NFAT(NFAT<sup>p</sup>); modulatory calcineurin-interacting protein (MCIP); phosphorylated MCIP on serine 112 (MCIP<sup>p</sup>); phosphorylated MCIP on both serine 112 and serine 108 (MCIP<sup>pp</sup>); big mitogenactivated protein kinase 1 (BMK1); glycogen synthase 3''β'' (GSK3''β''); the complex formed by MCIP and calcineurin (Complex1); the complex formed by MCIP<sup>pp</sup> and protein 14-3-3 (Complex2); the complex formed by NFAT<sup>p</sup> and protein 14-3-3 (Complex3); pressure overload (PO); hypertrophic stimuli (stress). The stress of PO is delivered by transverse aortic constriction (TAC).</span>