Estimation of Agonist Activity at G Protein-Coupled Receptors: Analysis of M2 Muscarinic Receptor Signaling through Gi/o,Gs, and G15

@article{Griffin2007EstimationOA,
  title={Estimation of Agonist Activity at G Protein-Coupled Receptors: Analysis of M2 Muscarinic Receptor Signaling through Gi/o,Gs, and G15},
  author={Michael T Griffin and Katherine W. Figueroa and Sarah Liller and Frederick J. Ehlert},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2007},
  volume={321},
  pages={1193 - 1207}
}
We developed novel methods for analyzing the concentration-response curve of an agonist to estimate the product of observed affinity and intrinsic efficacy, expressed relative to that of a standard agonist. This parameter, termed intrinsic relative activity (RAi), is most applicable for the analysis of responses at G protein-coupled receptors. RAi is equivalent to the potency ratios that agonists would exhibit in a hypothetical, highly sensitive assay in which all agonists behave as full… 
View on ASPET
jpet.aspetjournals.org
100 Citations
Highly Influential Citations
3
Background Citations
18
Methods Citations
15
Results Citations
3

Figures and Tables from this paper

100 Citations

Citation Type

Citation Type

Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes
TLDR
The results show that the RAi estimate is a useful receptor-dependent measure of agonist activity, and shows selectivity of McN-A-343 [4-I-[3-chlorophenyl]carbamoyloxy)-2-butynyltrimethylammnonium chloride for the M1 and M4 subtypes and selectiveness of pilocarpine for theM1 andM3 subtypes.
Intrinsic relative activities of κ opioid agonists in activating Gα proteins and internalizing receptor: Differences between human and mouse receptors.
On the analysis of ligand-directed signaling at G protein-coupled receptors
  • F. Ehlert
  • Biology
    Naunyn-Schmiedeberg's Archives of Pharmacology
  • 2008
TLDR
In this review, it is shown how the mathematics of the receptor theory can be used to measure the observed affinity and relative efficacy of protean ligands at G protein-coupled receptors.
A Novel Mechanism of G Protein-coupled Receptor Functional Selectivity
TLDR
Results are consistent with McN-A-343 being a bitopic orthosteric/allosteric ligand with the allosteric moiety engendering partial agonism and functional selectivity, and suggest a novel and largely unappreciated mechanism of “directed efficacy” wherebyfunctional selectivity may be engendered in a GPCR by utilizing an allosterics ligand to direct the signaling of an orthosterIC ligand encoded within the same molecule.
Estimation of ligand affinity constants for receptor states in functional studies involving the allosteric modulation of G protein-coupled receptors: implications for ligand bias.
Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
TLDR
The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
Fusion with Promiscuous Gα16 Subunit Reveals Signaling Bias at Muscarinic Receptors
TLDR
The data have shown that fusion proteins of muscarinic receptors with α-subunit of G-proteins can serve as a suitable tool for studying agonist bias, especially at non-preferential pathways.
Agonist binding, agonist affinity and agonist efficacy at G protein‐coupled receptors
  • P. Strange
  • Biology
    British journal of pharmacology
  • 2008
TLDR
It is shown that for many GPCRs, if receptor/G protein coupling is suppressed, experimental measurements of agonist affinity using ligand binding (Kobs) provide quite accurate measures of the agonist microscopic dissociation constant (KA).
A G Protein-Biased Ligand at the μ-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine
TLDR
The discovery of TRV130 is reported, a novel MOR G protein-biased ligand that successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology, and may be a safer and more tolerable therapeutic for treating severe pain.
Estimation of the receptor-state affinity constants of ligands in functional studies using wild type and constitutively active mutant receptors: Implications for estimation of agonist bias.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 40 REFERENCES
Muscarinic M2 Receptors Directly Activate Gq/11 and Gs G-Proteins
TLDR
Direct evidence of M2 receptor coupling with the α subunits of Gs and Gq/11 G-proteins is provided and induction of multiple receptor conformational states dependent on both the concentration and the nature of the agonist used is demonstrated.
A simple method for estimation of agonist activity at receptor subtypes: comparison of native and cloned M3 muscarinic receptors in guinea pig ileum and transfected cells.
TLDR
The analysis is validated with modeling techniques and has shown experimentally that the IRA values of muscarinic agonists for stimulating contractions in the guinea pig ileum (M3 response) are in excellent agreement with those measured in the phosphoinositide assay on Chinese hamster ovary cells expressing the M3muscarinic receptor.
Dual effects of muscarinic M2 acetylcholine receptors on the synthesis of cyclic AMP in CHO cells: dependence on time, receptor density and receptor agonists
TLDR
It is proposed that the Gs‐mediated stimulatory component of the effect of muscarinic M2 receptors on cyclic AMP synthesis only occurs if the density of activated receptors is high enough to saturate the Gi proteins and proportionate to the receptors' low affinity for theGs proteins.
Signaling through the muscarinic receptor-adenylate cyclase system of the heart is buffered against GTP over a range of concentrations.
TLDR
GTP increases receptor coupling efficiency and decreases agonist affinity and that these two effects oppose one another, so that the level of muscarinic agonist-mediated inhibition of adenylate cyclase activity remains relatively constant over a range of concentrations of GTP.
Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus.
TLDR
Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy.
Comparison of the pharmacological antagonism of M2 and M3 muscarinic receptors expressed in isolation and in combination.
Pharmacological analysis of the mode of interaction of McN-A-343 at atrial muscarinic M2 receptors.
Differential Coupling of Muscarinic M1, M2, and M3 Receptors to Phosphoinositide Hydrolysis in Urinary Bladder and Longitudinal Muscle of the Ileum of the Mouse
TLDR
A major role for the M3 receptor is suggested in eliciting phosphoinositide hydrolysis in the ileum and urinary bladder and minor roles for the Hinositol-labeled M1 and M2 in ilesum are suggested.
Stoichiometry and compartmentation in G protein-coupled receptor signaling: implications for therapeutic interventions involving G(s).
TLDR
Data showing the substantial excess of G(alphas) relative to both beta-adrenergic receptors and adenylyl cyclase is summarized and it is speculated that identification of genetic polymorphisms of and therapy targeted to components that are critical for determining efficacy will provide important future therapeutic strategies.
Analysis of Allosterism in Functional Assays
  • F. Ehlert
  • Biology
    Journal of Pharmacology and Experimental Therapeutics
  • 2005
TLDR
The utility of the RA value in quantifying allosteric effects is illustrated, which can be estimated easily from the agonist EC50 and Emax values, regardless of the shape of the concentration-response curve.
...
1
2
3
4
...