期刊
SCIENTIFIC REPORTS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-40993-w
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资金
- Czech Academy of Sciences [RVO:67985823]
- Grant Agency of the Czech Republic [17-16182 S]
Proper determination of agonist efficacy is essential in the assessment of agonist selectivity and signalling bias. Agonist efficacy is a relative term that is dependent on the system in which it is measured, especially being dependent on receptor expression level. The operational model (OM) of functional receptor agonism is a useful means for the determination of agonist functional efficacy using the maximal response to agonist and ratio of agonist functional potency to its equilibrium dissociation constant (K-A) at the active state of the receptor. However, the functional efficacy parameter tau is interdependent on two other parameters of OM; agonist's K-A and the highest response that could be evoked in the system by any stimulus (E-MAX). Thus, fitting of OM to functional response data is a tricky process. In this work we analyse pitfalls of fitting OM to experimental data and propose a rigorous fitting procedure where K-A and E-MAX are derived from half-efficient concentration of agonist and apparent maximal responses obtained from a series of functional response curves. Subsequently, OM with fixed K-A and E-MAX is fitted to functional response data to obtain tau. The procedure was verified at M-2 and M-4 muscarinic receptors fused with the G(15) G-protein alpha-subunit. The procedure, however, is applicable to any receptor-effector system.
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