/* * Modelling the calcium-calcineurin signalling network in cardiac * myocytes * * Model Status * * This CellML model runs in both PCEnv and COR to recreate the * published results. The units have been checked and they are * consistent. * * Model Structure * * ABSTRACT: Understanding of processes in which calcium signaling * is involved is of fundamental importance in systems biology * and has many applications in medicine. In this paper we have * studied the particular case of the complex calcium-calcineurin-MCIP-NFAT * signaling network in cardiac myocytes, the understanding of * which is critical for treatment of pathologic hypertrophy and * heart failure. By including some most recent experimental * * In 2006, Shin et al. published a paper which modelled the dual * role of MCIP in cardiac hypertrophy. In the study described * here, Cui and Kaandorp have extended this model to include more * recent and extensive experimental data. They used Cellerator, * an open source software, to automatically generate the equations, * and the model was subsequently translated into CellML to facilitate * future model exchange, reuse and implementation. * * model diagram * * [[Image file: cui_calcium_2008.png]] * * A schematic diagram of the Ca2+-calcineurin-MCIP-NFAT signalling * networks in cardiac myocytes described by the model. Abbreviations: * calmodulin (CaM); calcineurin (CaN); activated calcineurin (CaN*); * nuclear factor of activated T-cells (NFAT); phosphorylated NFAT * (NFATP); modulatory calcineurin-interacting protein (MCIP); * phosphorylated MCIP on serine 112 (MCIPP); phosphorylated MCIP * on both serine 112 and serine 108 (MCIPPP); big mitogen-activated * protein kinase 1 (BMK1); glycogen synthase 3 * * The original book chapter reference is cited below: * * Simulating Complex Calcium-Calcineurin Signaling Network, Jiangjun * Cui and Jaap A. Kaandorp, 2008, Lecture Notes in Computer Science, * 5013, 110-119, PubMed ID: 16445978. */ import nsrunit; unit conversion on; unit minute=60 second^1; //Warning: unit micromolar_ renamed from micromolar, as the latter is predefined in JSim with different fundamental units. unit micromolar_=1E-6 meter^(-3)*mole^1; unit flux=1.6666667E-5 meter^(-3)*second^(-1)*mole^1; unit first_order_rate_constant=.01666667 second^(-1); unit second_order_rate_constant=16.66666667 meter^3*second^(-1)*mole^(-1); unit fifth_order_rate_constant=1.6666667E10 meter^12*second^(-1)*mole^(-4); math main { realDomain time minute; time.min=0; extern time.max; extern time.delta; real BMK1(time) micromolar_; when(time=time.min) BMK1=0.012; real v10a(time) flux; real v10b(time) flux; real MRNA(time) micromolar_; when(time=time.min) MRNA=3.33E-4; real v18(time) flux; real v19(time) flux; real NFATc(time) micromolar_; when(time=time.min) NFATc=2E-5; real v1(time) flux; real v14(time) flux; real v15(time) flux; real NFATn(time) micromolar_; when(time=time.min) NFATn=4.99E-4; real v16(time) flux; real v17(time) flux; real NFATpc(time) micromolar_; when(time=time.min) NFATpc=4.94E-3; real v2(time) flux; real v9(time) flux; real NFATpn(time) micromolar_; when(time=time.min) NFATpn=8.01E-5; real GSK3betac(time) micromolar_; when(time=time.min) GSK3betac=0.17; real v3(time) flux; real v12a(time) flux; real v12b(time) flux; real v15a(time) flux; real v15b(time) flux; real GSK3betan(time) micromolar_; when(time=time.min) GSK3betan=0.339; real v17a(time) flux; real v17b(time) flux; real CaNc(time) micromolar_; when(time=time.min) CaNc=0.91; real v6(time) flux; real CaNc_star(time) micromolar_; when(time=time.min) CaNc_star=0.0275; real v4(time) flux; real v7(time) flux; real v11a(time) flux; real v11b(time) flux; real v13a(time) flux; real v13b(time) flux; real v14a(time) flux; real v14b(time) flux; real CaNn_star(time) micromolar_; when(time=time.min) CaNn_star=0.0568; real v16a(time) flux; real v16b(time) flux; real CaNn(time) micromolar_; when(time=time.min) CaNn=0.0057; real CaM(time) micromolar_; when(time=time.min) CaM=25.2; real v5(time) flux; real CaMCa(time) micromolar_; when(time=time.min) CaMCa=7.88E-7; real MCIP(time) micromolar_; when(time=time.min) MCIP=2.15E-4; real v10(time) flux; real v11(time) flux; real MCIPp(time) micromolar_; when(time=time.min) MCIPp=7.76E-3; real v12(time) flux; real v13(time) flux; real MCIPpp(time) micromolar_; when(time=time.min) MCIPpp=0.0798; real v8(time) flux; real Comp1(time) micromolar_; when(time=time.min) Comp1=5.21E-3; real Comp2(time) micromolar_; when(time=time.min) Comp2=0.283; real Comp3(time) micromolar_; when(time=time.min) Comp3=0.014; real P1433(time) micromolar_; when(time=time.min) P1433=0.708; real MCIP_BMK1(time) micromolar_; when(time=time.min) MCIP_BMK1=2.14E-5; real MCIPp_CaNc_star(time) micromolar_; when(time=time.min) MCIPp_CaNc_star=1.07E-4; real MCIPp_GSK3betac(time) micromolar_; when(time=time.min) MCIPp_GSK3betac=1.1E-3; real MCIPpp_CaNc_star(time) micromolar_; when(time=time.min) MCIPpp_CaNc_star=1.1E-3; real NFATpc_CaNc_star(time) micromolar_; when(time=time.min) NFATpc_CaNc_star=8.15E-5; real NFATc_GSK3betac(time) micromolar_; when(time=time.min) NFATc_GSK3betac=1.36E-6; real NFATpn_CaNn_star(time) micromolar_; when(time=time.min) NFATpn_CaNn_star=2.27E-6; real NFATn_GSK3betan(time) micromolar_; when(time=time.min) NFATn_GSK3betan=8.46E-5; real k29 first_order_rate_constant; k29=0.4; real k30 first_order_rate_constant; k30=0.1; real k31 first_order_rate_constant; k31=0.1; real k32 first_order_rate_constant; k32=0.05; real k33 first_order_rate_constant; k33=0.114; real k34 first_order_rate_constant; k34=0.0552; real Ca micromolar_; Ca=0.2; real k1 fifth_order_rate_constant; k1=5; real k2 first_order_rate_constant; k2=100; real k3 second_order_rate_constant; k3=2760; real k4 first_order_rate_constant; k4=0.072; real k5 second_order_rate_constant; k5=50; real k6 first_order_rate_constant; k6=0.0567; real k19 second_order_rate_constant; k19=0.5; real k20 first_order_rate_constant; k20=0.1; real k27 second_order_rate_constant; k27=0.4; real k28 first_order_rate_constant; k28=0.1; real k7 second_order_rate_constant; k7=5; real k8 first_order_rate_constant; k8=0.1; real k9 first_order_rate_constant; k9=0.5; real k10 second_order_rate_constant; k10=0.1; real k11 first_order_rate_constant; k11=0.1; real k12 first_order_rate_constant; k12=0.1; real k13 second_order_rate_constant; k13=0.5; real k14 first_order_rate_constant; k14=0.5; real k15 first_order_rate_constant; k15=0.1; real k16 second_order_rate_constant; k16=0.1; real k17 first_order_rate_constant; k17=0.1; real k18 first_order_rate_constant; k18=0.1; real k21 second_order_rate_constant; k21=0.15; real k22 first_order_rate_constant; k22=0.15; real k23 first_order_rate_constant; k23=0.15; real k24 second_order_rate_constant; k24=0.1; real k25 first_order_rate_constant; k25=0.15; real k26 first_order_rate_constant; k26=0.1; real k35 second_order_rate_constant; k35=0.15; real k36 first_order_rate_constant; k36=0.1; real k37 first_order_rate_constant; k37=0.2; real k38 second_order_rate_constant; k38=0.1; real k39 first_order_rate_constant; k39=0.1; real k40 first_order_rate_constant; k40=0.1; real k41 first_order_rate_constant; k41=0.02; real k42 first_order_rate_constant; k42=0.03; real t_half minute; t_half=15; real k43 first_order_rate_constant; k43=0.03; // // BMK1:time=(v10b-v10a); // MRNA:time=(v19-v18); // NFATc:time=(v14-(v1+v15)); // NFATn:time=(v1+v16-(v17+v18)); // NFATpc:time=(v2+v15-(v9+v14)); // NFATpn:time=(v17-(v2+v16)); // GSK3betac:time=(v12b+v15b-(v3+v12a+v15a)); // GSK3betan:time=(v3+v17b-v17a); // CaNc:time=((-1)*v6); // CaNc_star:time=(v6+v11b+v13b+v14b-(v4+v7+v11a+v13a+v14a)); // CaNn_star:time=(v4+v16b-v16a); // CaNn:time=((-1)*v6); // CaM:time=((-1)*v5); // CaMCa:time=(v5-v6); // MCIP:time=(v11-(v7+v10+v19)); // MCIPp:time=(v10+v13-(v11+v12)); // MCIPpp:time=(v12-(v8+v13)); // Comp1:time=v7; // Comp2:time=v8; // Comp3:time=v9; // P1433:time=((-1)*(v8+v9)); // MCIP_BMK1:time=(v10a-v10b); // MCIPp_CaNc_star:time=(v11a-v11b); // MCIPp_GSK3betac:time=(v12a-v12b); // MCIPpp_CaNc_star:time=(v13a-v13b); // NFATpc_CaNc_star:time=(v14a-v14b); // NFATc_GSK3betac:time=(v15a-v15b); // NFATpn_CaNn_star:time=(v16a-v16b); // NFATn_GSK3betan:time=(v17a-v17b); // v1=(k29*NFATc); // v2=(k30*NFATpn); // v3=(k31*GSK3betac-k32*GSK3betan); // v4=(k33*CaNc_star-k34*CaNn_star); // v5=(k1*CaM*Ca^4-k2*CaMCa); // v6=(k3*CaMCa*CaNc-k4*CaNc_star); // v7=(k5*CaNc_star*MCIP-k6*Comp1); // v8=(k19*P1433*MCIPpp-k20*Comp2); // v9=(k27*NFATpc*P1433-k28*Comp3); // v10a=(k7*MCIP*BMK1-k8*MCIP_BMK1); v10b=(k9*MCIP_BMK1); v10=(v10a+v10b); // v11a=(k10*MCIPp*CaNc_star-k11*MCIPp_CaNc_star); v11b=(k12*MCIPp_CaNc_star); v11=(v11a+v11b); // v12a=(k13*MCIPp*GSK3betac-k14*MCIPp_GSK3betac); v12b=(k15*MCIPp_GSK3betac); v12=(v12a+v12b); // v13a=(k16*MCIPpp*CaNc_star-k17*MCIPpp_CaNc_star); v13b=(k18*MCIPpp_CaNc_star); v13=(v13a+v13b); // v14a=(k21*NFATpc*CaNc_star-k22*NFATpc_CaNc_star); v14b=(k23*NFATpc_CaNc_star); v14=(v14a+v14b); // v15a=(k24*NFATc*GSK3betac-k25*NFATc_GSK3betac); v15b=(k26*NFATc_GSK3betac); v15=(v15a+v15b); // v16a=(k35*NFATpn*CaNn_star-k36*NFATpn_CaNn_star); v16b=(k37*NFATpn_CaNn_star); v16=(v16a+v16b); // v17a=(k38*NFATn*GSK3betan-k39*NFATn_GSK3betan); v17b=(k40*NFATn_GSK3betan); v17=(v17a+v17b); // v18=(k41*NFATn-k42*MRNA); // v19=(k43*MRNA-ln(2)/t_half*MCIP); // }