Diffusion-limited reactions in G-protein activation: unexpected consequences of antagonist and agonist competition.
In this work, we ask whether the simultaneous movement of agonist and antagonist among surface receptors (i.e. continually associating and dissociating from individual receptors according to specified kinetics) has any unexpected consequences for G-protein activation and receptor desensitization. A Monte Carlo model framework is used to track the diffusion and reaction of individual receptors, allowing the requirement for receptors and G-proteins or receptors and kinases to find each other by diffusion (collision coupling) to be implemented explicitly. We find that at constant agonist occupancy the effect of an antagonist on both G-protein activation and the ratio of G-protein activation to receptor desensitization can be modulated by varying the antagonist dissociation kinetics. The explanation for this effect is that antagonist dissociation kinetics influence the ability of agonists to access particular receptors and thus reach G-proteins and kinases near those receptors. Relevant parameter ranges for observation of these effects are identified. These results are useful for understanding experimental and therapeutic situations when both agonist and antagonist are present, and in addition may offer new insights into insurmountable antagonism.
Brinkerhoff
Christopher J
CJ
Department of Chemical Engineering, University of Michigan, H.H. Dow Building, 2300 Hayward Street, Ann Arbor, MI 48109-2136, USA. brinkerh@umich.edu
Choi
Ji Sun
JS
Linderman
Jennifer J
JJ
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D004058:Diffusion; D019204:GTP-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D011956:Receptors, Cell Surface; D010770:Phosphotransferases; D019204:GTP-Binding Proteins