Both Ligand- and Cell-Specific Parameters Control Ligand.docVIP

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Both Ligand- and Cell-Specific Parameters Control Ligand.doc

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Both Ligand- and Cell-Specific Parameters Control Ligand.doc

Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G protein Coupled Receptor Signaling by Tamara L. Kinzer-Ursem and Jennifer J. Linderman Supporting Text - Cubic Ternary Complex Activation Model (cTCAM) The reactions and the accompanying rate constants necessary to describe the cTCAM are shown in Fig. S1. Model detail and assumptions are explained in this supporting text. Differential equations describing the cTCAM were written according to mass action kinetics and are also outlined below (Eqns. S.19 – S.30). G-protein activation/inactivation steps Under physiological conditions, activation of G protein by an active receptor (R*) initiates a multi-step process of GDP dissociation, GTP association, and dissociation of the G protein heterotrimer into G( and G(( subunits. These elementary processes are represented in the cTCAM (Fig. 1 and A1) as a single step with active receptor-G protein complexes (R*G and LR*G) activating G protein with the rate constant kGact in accordance with findings that show the dissociation of GDP from the G( protein subunit to be the rate limiting step [1,2]. It is assumed that rate constant of G protein activation (kGact) is the same or similar for both constitutively active receptor/G-protein complexes (R*G) and ligand-associated active receptor/G protein complexes (LR*G). GαGTP is considered to be the response signal although it is known that Gβγ also couples to and activates signal transduction proteins [3,4]. The active G(GTP subunit is deactivated when the nucleotide is hydrolyzed to form G(GDP with a rate constant kGTP. This rate constant can vary over several 100 fold depending on the intrinsic GTPase activity of the G( subunit or the presence of RGS proteins in the system [5,6]. Recombination of the G(GDP and G(( subunits to form free G protein occurs with rate constant kG. Assumptions regarding rate constants describing ligand, receptor, and G-protein interactions When the system is at e