Journal
JOURNAL OF THEORETICAL BIOLOGY
Volume 251, Issue 4, Pages 561-569Publisher
ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jtbi.2008.01.002
Keywords
G-protein coupled receptor; desensitization; simulation; model
Categories
Funding
- NIGMS NIH HHS [T32 GM145304, R01 GM062930-03, R01 GM062930] Funding Source: Medline
Ask authors/readers for more resources
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. (c) 2008 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available