<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : bi_PLC_beta_pathway_1999.xml
CREATED : 6th November 2001
LAST MODIFIED : 9th April 2003
AUTHOR : Catherine Lloyd
Department of Engineering Science
The University of Auckland
MODEL STATUS : This model conforms to the CellML 1.0 Specification released on
10th August 2001, and the 16/01/2002 CellML Metadata 1.0 Specification.
DESCRIPTION : This file contains a CellML description of the PLC-beta pathway
model from Bhalla and Iyengar (1999).
CHANGES:
22/01/2002 - AAC - Updated metadata to conform to the 16/1/02 CellML Metadata
1.0 Specification.
18/07/2002 - CML - Added more metadata.
09/04/2003 - AAC - Added publication date information.
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="bhalla_model_1999" name="bhalla_model_1999">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>The Phospholipase C (PLC) (beta) Pathway Model from Bhalla and Iyengar</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This version of the CellML model describes the PLC (beta) pathway component of the Bhalla-Iyengar model. This model is able to be solved but does not give the correct results as it is not connected to the other modules of the pathway. ValidateCellML verifies this model as valid CellML but detects unit inconsistencies.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: Many distinct signaling pathways allow the cell to receive, process, and respond to information. Often, components of different pathways interact, resulting in signaling networks. Biochemical signaling networks were constructed with experimentally obtained constants and analyzed by computational methods to understand their role in complex biological processes. These networks exhibit emergent properties such as integration of signals across multiple time scales, generation of distinct outputs depending on input strength and duration, and self-sustaining feedback loops. Feedback can result in bistable behavior with discrete steady-state activities, well-defined input thresholds for transition between states and prolonged signal output, and signal modulation in response to transient stimuli. These properties of signaling networks raise the possibility that information for "learned behavior" of biological systems may be stored within intracellular biochemical reactions that comprise signaling pathways.
</para>
<para>
The original paper reference is cited below:
</para>
<para>
Emergent properties of networks of biological signaling pathways. Bhalla US, Iyengar R.
<emphasis>Science</emphasis> 1999 Jan 15; 283(5400); 381-7. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9888852&dopt=Abstract">PubMed ID: 9888852</ulink>
</para>
<informalfigure float="0" id="fig_pathway_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="bhalla_iyengar_PLC_beta_1999.png"/>
</imageobject>
</mediaobject>
<caption>A rendering of the PLC (beta) pathway component of the Bhalla-Iyengar model.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<!--
We start the model definition with a definition of some named
sets of units for use throughout the model.
-->
<units name="micromolar">
<unit units="mole" prefix="micro"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="flux">
<unit units="micromolar"/>
<unit units="second" exponent="-1"/>
</units>
<units name="first_order_rate_constant_units">
<unit units="second" exponent="-1"/>
</units>
<units name="second_order_rate_constant_units">
<unit units="micromolar" exponent="-1"/>
<unit units="second" exponent="-1"/>
</units>
<component name="global_variables">
<variable units="second" public_interface="out" name="time"/>
</component>
<component cmeta:id="DAG" name="DAG">
<variable units="micromolar" public_interface="out" name="DAG"/>
<variable units="flux" public_interface="in" name="delta_DAG_rxn2"/>
<variable units="flux" public_interface="in" name="delta_DAG_rxn3"/>
<variable units="flux" public_interface="in" name="delta_DAG_rxn0"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>DAG</ci>
</apply>
<apply>
<plus/>
<ci>delta_DAG_rxn2</ci>
<ci>delta_DAG_rxn3</ci>
<ci>delta_DAG_rxn0</ci>
</apply>
</apply>
</math>
</component>
<component name="PC">
<variable units="micromolar" public_interface="out" name="PC"/>
<variable units="flux" public_interface="in" name="delta_PC_rxn0"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PC</ci>
</apply>
<ci>delta_PC_rxn0</ci>
</apply>
</math>
</component>
<component cmeta:id="IP3" name="IP3">
<variable units="micromolar" public_interface="out" name="IP3"/>
<variable units="flux" public_interface="in" name="delta_IP3_rxn2"/>
<variable units="flux" public_interface="in" name="delta_IP3_rxn3"/>
<variable units="flux" public_interface="in" name="delta_IP3_rxn1"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>IP3</ci>
</apply>
<apply>
<plus/>
<ci>delta_IP3_rxn2</ci>
<ci>delta_IP3_rxn3</ci>
<ci>delta_IP3_rxn1</ci>
</apply>
</apply>
</math>
</component>
<component name="Inositol">
<variable units="micromolar" public_interface="out" name="Inositol"/>
<variable units="flux" public_interface="in" name="delta_Inositol_rxn1"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Inositol</ci>
</apply>
<ci>delta_Inositol_rxn1</ci>
</apply>
</math>
</component>
<component cmeta:id="PLC" name="PLC">
<variable units="micromolar" public_interface="out" name="PLC" initial_value="0.8"/>
<variable units="flux" public_interface="in" name="delta_PLC_rxn4"/>
<variable units="flux" public_interface="in" name="delta_PLC_rxn5"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PLC</ci>
</apply>
<apply>
<plus/>
<ci>delta_PLC_rxn4</ci>
<ci>delta_PLC_rxn5</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="Ca" name="Ca">
<variable units="micromolar" public_interface="out" name="Ca" initial_value="1.0"/>
<variable units="flux" public_interface="in" name="delta_Ca_rxn4"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca</ci>
</apply>
<ci>delta_Ca_rxn4</ci>
</apply>
</math>
</component>
<component name="Ca_PLC">
<variable units="micromolar" public_interface="out" name="Ca_PLC"/>
<variable units="flux" public_interface="in" name="delta_Ca_PLC_rxn4"/>
<variable units="flux" public_interface="in" name="delta_Ca_PLC_rxn8"/>
<variable units="flux" public_interface="in" name="delta_Ca_PLC_rxn7"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_PLC</ci>
</apply>
<apply>
<plus/>
<ci>delta_Ca_PLC_rxn4</ci>
<ci>delta_Ca_PLC_rxn8</ci>
<ci>delta_Ca_PLC_rxn7</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="PIP2" name="PIP2">
<variable units="micromolar" public_interface="out" name="PIP2" initial_value="10.0"/>
<variable units="flux" public_interface="in" name="delta_PIP2_rxn2"/>
<variable units="flux" public_interface="in" name="delta_PIP2_rxn3"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>PIP2</ci>
</apply>
<apply>
<plus/>
<ci>delta_PIP2_rxn2</ci>
<ci>delta_PIP2_rxn3</ci>
</apply>
</apply>
</math>
</component>
<component cmeta:id="Gq" name="Gq">
<variable units="micromolar" public_interface="out" name="Gq" initial_value="1.0"/>
<variable units="flux" public_interface="in" name="delta_Gq_rxn8"/>
<variable units="flux" public_interface="in" name="delta_Gq_rxn5"/>
<variable units="flux" public_interface="in" name="delta_Gq_rxn6"/>
<variable units="flux" public_interface="in" name="delta_Gq_rxn7"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gq</ci>
</apply>
<apply>
<plus/>
<ci>delta_Gq_rxn8</ci>
<ci>delta_Gq_rxn5</ci>
<ci>delta_Gq_rxn6</ci>
<ci>delta_Gq_rxn7</ci>
</apply>
</apply>
</math>
</component>
<component name="Gq_PLC">
<variable units="micromolar" public_interface="out" name="Gq_PLC"/>
<variable units="flux" public_interface="in" name="delta_Gq_PLC_rxn5"/>
<variable units="flux" public_interface="in" name="delta_Gq_PLC_rxn6"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gq_PLC</ci>
</apply>
<apply>
<plus/>
<ci>delta_Gq_PLC_rxn5</ci>
<ci>delta_Gq_PLC_rxn6</ci>
</apply>
</apply>
</math>
</component>
<component name="Ca_Gq_PLC">
<variable units="micromolar" public_interface="out" name="Ca_Gq_PLC" initial_value="1.0"/>
<variable units="flux" public_interface="in" name="delta_Ca_Gq_PLC_rxn6"/>
<variable units="flux" public_interface="in" name="delta_Ca_Gq_PLC_rxn7"/>
<variable units="flux" public_interface="in" name="delta_Ca_Gq_PLC_rxn8"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_Gq_PLC</ci>
</apply>
<apply>
<plus/>
<ci>delta_Ca_Gq_PLC_rxn6</ci>
<ci>delta_Ca_Gq_PLC_rxn7</ci>
<ci>delta_Ca_Gq_PLC_rxn8</ci>
</apply>
</apply>
</math>
</component>
<component name="reaction0">
<variable units="micromolar" public_interface="in" name="DAG"/>
<variable units="micromolar" public_interface="in" name="PC"/>
<variable units="flux" public_interface="out" name="delta_DAG_rxn0"/>
<variable units="flux" public_interface="out" name="delta_PC_rxn0"/>
<variable units="first_order_rate_constant_units" name="k0" initial_value="0.15"/>
<variable units="flux" name="rate"/>
<reaction reversible="no">
<variable_ref variable="DAG">
<role stoichiometry="1" delta_variable="delta_DAG_rxn0" role="reactant"/>
</variable_ref>
<variable_ref variable="PC">
<role stoichiometry="1" delta_variable="delta_PC_rxn0" role="product"/>
</variable_ref>
<variable_ref variable="rate">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>rate</ci>
<apply>
<times/>
<ci>k0</ci>
<ci>DAG</ci>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
</component>
<component name="reaction1">
<variable units="micromolar" public_interface="in" name="IP3"/>
<variable units="micromolar" public_interface="in" name="Inositol"/>
<variable units="flux" public_interface="out" name="delta_IP3_rxn1"/>
<variable units="flux" public_interface="out" name="delta_Inositol_rxn1"/>
<variable units="first_order_rate_constant_units" name="k1" initial_value="2.5"/>
<variable units="flux" name="rate"/>
<reaction reversible="no">
<variable_ref variable="IP3">
<role stoichiometry="1" delta_variable="delta_IP3_rxn1" role="reactant"/>
</variable_ref>
<variable_ref variable="Inositol">
<role stoichiometry="1" delta_variable="delta_Inositol_rxn1" role="product"/>
</variable_ref>
<variable_ref variable="rate">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>rate</ci>
<apply>
<times/>
<ci>k1</ci>
<ci>IP3</ci>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
</component>
<component name="reaction2">
<variable units="micromolar" public_interface="in" name="PIP2"/>
<variable units="micromolar" public_interface="in" name="DAG"/>
<variable units="micromolar" public_interface="in" name="IP3"/>
<variable units="micromolar" public_interface="in" name="Ca_PLC"/>
<variable units="flux" public_interface="out" name="delta_PIP2_rxn2"/>
<variable units="flux" public_interface="out" name="delta_DAG_rxn2"/>
<variable units="flux" public_interface="out" name="delta_IP3_rxn2"/>
<variable units="micromolar" name="km2" initial_value="5.0"/>
<variable units="first_order_rate_constant_units" name="vmax2" initial_value="48.0"/>
<variable units="flux" name="rate"/>
<reaction reversible="no">
<variable_ref variable="PIP2">
<role stoichiometry="1" delta_variable="delta_PIP2_rxn2" role="reactant"/>
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<variable_ref variable="DAG">
<role stoichiometry="1" delta_variable="delta_DAG_rxn2" role="product"/>
</variable_ref>
<variable_ref variable="IP3">
<role stoichiometry="1" delta_variable="delta_IP3_rxn2" role="product"/>
</variable_ref>
<variable_ref variable="Ca_PLC">
<role role="catalyst"/>
</variable_ref>
<variable_ref variable="rate">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>rate</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>PIP2</ci>
<ci>vmax2</ci>
</apply>
<apply>
<plus/>
<ci>km2</ci>
<ci>PIP2</ci>
</apply>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
</component>
<component name="reaction3">
<variable units="micromolar" public_interface="in" name="PIP2"/>
<variable units="micromolar" public_interface="in" name="DAG"/>
<variable units="micromolar" public_interface="in" name="IP3"/>
<variable units="micromolar" public_interface="in" name="Ca_Gq_PLC"/>
<variable units="flux" public_interface="out" name="delta_PIP2_rxn3"/>
<variable units="flux" public_interface="out" name="delta_DAG_rxn3"/>
<variable units="flux" public_interface="out" name="delta_IP3_rxn3"/>
<variable units="micromolar" name="km3" initial_value="19.84166667"/>
<variable units="first_order_rate_constant_units" name="vmax3" initial_value="10.0"/>
<variable units="flux" name="rate"/>
<reaction reversible="no">
<variable_ref variable="PIP2">
<role stoichiometry="1" delta_variable="delta_PIP2_rxn3" role="reactant"/>
</variable_ref>
<variable_ref variable="DAG">
<role stoichiometry="1" delta_variable="delta_DAG_rxn3" role="product"/>
</variable_ref>
<variable_ref variable="IP3">
<role stoichiometry="1" delta_variable="delta_IP3_rxn3" role="product"/>
</variable_ref>
<variable_ref variable="Ca_Gq_PLC">
<role role="catalyst"/>
</variable_ref>
<variable_ref variable="rate">
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<math xmlns="http://www.w3.org/1998/Math/MathML">
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<eq/>
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<apply>
<divide/>
<apply>
<times/>
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<ci>vmax3</ci>
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<plus/>
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<ci>PIP2</ci>
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</math>
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</component>
<component name="reaction4">
<variable units="micromolar" public_interface="in" name="PLC"/>
<variable units="micromolar" public_interface="in" name="Ca"/>
<variable units="micromolar" public_interface="in" name="Ca_PLC"/>
<variable units="flux" public_interface="out" name="delta_PLC_rxn4"/>
<variable units="flux" public_interface="out" name="delta_Ca_rxn4"/>
<variable units="flux" public_interface="out" name="delta_Ca_PLC_rxn4"/>
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<variable units="flux" name="rate"/>
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</variable_ref>
<variable_ref variable="Ca">
<role stoichiometry="1" direction="forward" delta_variable="delta_Ca_rxn4" role="reactant"/>
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<variable_ref variable="Ca_PLC">
<role stoichiometry="1" direction="forward" delta_variable="delta_Ca_PLC_rxn4" role="product"/>
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<variable_ref variable="rate">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
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<eq/>
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<apply>
<plus/>
<apply>
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<ci>k4</ci>
<ci>PLC</ci>
<ci>Ca</ci>
</apply>
<apply>
<minus/>
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<ci>k4_</ci>
<ci>Ca_PLC</ci>
</apply>
</apply>
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</apply>
</math>
</role>
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</component>
<component name="reaction5">
<variable units="micromolar" public_interface="in" name="PLC"/>
<variable units="micromolar" public_interface="in" name="Gq"/>
<variable units="micromolar" public_interface="in" name="Gq_PLC"/>
<variable units="flux" public_interface="out" name="delta_PLC_rxn5"/>
<variable units="flux" public_interface="out" name="delta_Gq_rxn5"/>
<variable units="flux" public_interface="out" name="delta_Gq_PLC_rxn5"/>
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<variable units="first_order_rate_constant_units" name="k5_" initial_value="1.0"/>
<variable units="flux" name="rate"/>
<reaction reversible="yes">
<variable_ref variable="PLC">
<role stoichiometry="1" direction="forward" delta_variable="delta_PLC_rxn5" role="reactant"/>
</variable_ref>
<variable_ref variable="Gq">
<role stoichiometry="1" direction="forward" delta_variable="delta_Gq_rxn5" role="reactant"/>
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<variable_ref variable="Gq_PLC">
<role stoichiometry="1" direction="forward" delta_variable="delta_Gq_PLC_rxn5" role="product"/>
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<variable_ref variable="rate">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
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<apply>
<plus/>
<apply>
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<ci>k5</ci>
<ci>PLC</ci>
<ci>Gq</ci>
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<apply>
<minus/>
<apply>
<times/>
<ci>k5_</ci>
<ci>Gq_PLC</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
</component>
<component name="reaction6">
<variable units="micromolar" public_interface="in" name="Gq"/>
<variable units="micromolar" public_interface="in" name="Gq_PLC"/>
<variable units="micromolar" public_interface="in" name="Ca_Gq_PLC"/>
<variable units="flux" public_interface="out" name="delta_Gq_rxn6"/>
<variable units="flux" public_interface="out" name="delta_Gq_PLC_rxn6"/>
<variable units="flux" public_interface="out" name="delta_Ca_Gq_PLC_rxn6"/>
<variable units="second_order_rate_constant_units" name="k6" initial_value="0.00005"/>
<variable units="first_order_rate_constant_units" name="k6_" initial_value="1.0"/>
<variable units="flux" name="rate"/>
<reaction reversible="yes">
<variable_ref variable="Gq">
<role stoichiometry="1" direction="forward" delta_variable="delta_Gq_rxn6" role="reactant"/>
</variable_ref>
<variable_ref variable="Gq_PLC">
<role stoichiometry="1" direction="forward" delta_variable="delta_Gq_PLC_rxn6" role="reactant"/>
</variable_ref>
<variable_ref variable="Ca_Gq_PLC">
<role stoichiometry="1" direction="forward" delta_variable="delta_Ca_Gq_PLC_rxn6" role="product"/>
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<variable_ref variable="rate">
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<math xmlns="http://www.w3.org/1998/Math/MathML">
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<apply>
<plus/>
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<ci>Gq</ci>
<ci>Gq_PLC</ci>
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<apply>
<minus/>
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<ci>Ca_Gq_PLC</ci>
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</component>
<component name="reaction7">
<variable units="micromolar" public_interface="in" name="Ca_PLC"/>
<variable units="micromolar" public_interface="in" name="Gq"/>
<variable units="micromolar" public_interface="in" name="Ca_Gq_PLC"/>
<variable units="flux" public_interface="out" name="delta_Ca_PLC_rxn7"/>
<variable units="flux" public_interface="out" name="delta_Gq_rxn7"/>
<variable units="flux" public_interface="out" name="delta_Ca_Gq_PLC_rxn7"/>
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<variable units="first_order_rate_constant_units" name="k7_" initial_value="1.0"/>
<variable units="flux" name="rate"/>
<reaction reversible="yes">
<variable_ref variable="Ca_PLC">
<role stoichiometry="1" direction="forward" delta_variable="delta_Ca_PLC_rxn7" role="reactant"/>
</variable_ref>
<variable_ref variable="Gq">
<role stoichiometry="1" direction="forward" delta_variable="delta_Gq_rxn7" role="reactant"/>
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<connection>
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<connection>
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<connection>
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<connection>
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<vCard:FN>Catherine Lloyd</vCard:FN>
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The University of Auckland, Auckland Bioengineering Institute
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<dcterms:alternative>inositol-1,4,5-phosphate</dcterms:alternative>
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<dcterms:alternative>calcium</dcterms:alternative>
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This is the CellML description of Bhalla and Iyengar's mathematical
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Phosphatidylinositol-4,5-bisphosphate
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<dcterms:alternative>diacylglycerol</dcterms:alternative>
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<vCard:Given>Ravi</vCard:Given>
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Emergent Properties of Networks of Biological Signaling Pathways
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