Theoretical effects of single and multiple transducer receptor coupling proteins on estimates of the relative potency of agonists.

A mathematical model is presented that simulates the steady state kinetics of agonists interacting with a promiscuous receptor. The model system consists of a single receptor that forms a ternary complex with either of two transducer proteins (G proteins). At a given agonist concentration, the concentrations of the two ternary complexes are determined by the relative quantities of the two G proteins and the ratio of the dissociation constants for the two ternary complexes. Accordingly, the potency of an agonist is dependent upon the relative quantities of the G proteins. If receptors are truly promiscuous and if the distribution of G proteins varies with tissue type, then the agonist potency ratio would be tissue dependent as well as receptor dependent. Experimental data from literature studies are reviewed in the context of the promiscuous receptor model, and implications of the model regarding pharmacologic classification of receptors are discussed.

• Publication year

  1989

• Venue

  Molecular Pharmacology

• Publication date

  1989-02-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/s0026-895x(25)10934-6PMID 2537459
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The collisional limit: an important consideration for membrane‐associated enzymes and receptors

  1988cited by this paper
• Are receptors promiscuous? Intrinsic efficacy as a transduction phenomenon.

  1988cited by this paper
• Phosphatidic acid may stimulate membrane receptors mediating adenylate cyclase inhibition and phospholipid breakdown in 3T3 fibroblasts.

  1987cited by this paper
• An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover.

  1987cited by this paper
• Activation of two signal-transduction systems in hepatocytes by glucagon

  1986cited by this paper
• Differences in muscarinic receptor reserve for inhibition of adenylate cyclase and stimulation of phosphoinositide hydrolysis in chick heart cells.

  1986cited by this paper
• Reconstitution of the muscarinic acetylcholine receptor. Guanine nucleotide-sensitive high affinity binding of agonists to purified muscarinic receptors reconstituted with GTP-binding proteins (Gi and Go).

  1986cited by this paper
• Functional reconstitution of the alpha 2-adrenergic receptor with guanine nucleotide regulatory proteins in phospholipid vesicles.

  1986cited by this paper
• Receptor-mediated inhibition of adenylate cyclase and stimulation of arachidonic acid release in 3T3 fibroblasts. Selective susceptibility to islet-activating protein, pertussis toxin.

  1985cited by this paper
• GTP-binding proteins couple cardiac muscarinic receptors to a K channel

  1985cited by this paper
• The quantification of relative efficacy of agonists.

  1985cited by this paper
• Pertussis toxin separates two muscarinic receptor-effector mechanisms in the striatum.

  1985cited by this paper
• Activation of the inhibitory GTP-binding protein of adenylate cyclase, Gi, by beta-adrenergic receptors in reconstituted phospholipid vesicles.

  1984cited by this paper
• The classification of drugs and drug receptors in isolated tissues.

  1984cited by this paper
• Functional uncoupling of muscarinic receptors from adenylate cyclase in rat cardiac membranes by the active component of islet-activating protein, pertussis toxin.

  1983cited by this paper
• Operational models of pharmacological agonism

  1983cited by this paper
• Review important concepts of receptor theory.

  1982cited by this paper
• Is prenalterol (H133/80) really a selective beta 1 adrenoceptor agonist? Tissue selectivity resulting from differences in stimulus-response relationships.

  1980cited by this paper
• The mobile receptor hypothesis and "cooperativity" of hormone binding. Application to insulin.

  1976cited by this paper
• Membrane receptors.

  1974cited by this paper
• Receptor Occupancy and Tissue Response

  1956cited by this paper
• Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory.

  1954cited by this paper

• Biased Agonism at β-Adrenoceptor Subtypes: A Drug Development Perspective.

  2025cites this paper
• Agonism and Biased Signaling.

  2025cites this paper
• An Industrial Perspective on Ligand Bias in GPCR Drug Discovery.

  2025cites this paper
• Bias translation: The final frontier?

  2024cites this paper
• Introduction: A Short History of Adrenoceptor Research.

  2024cites this paper
• Know your molecule: pharmacological characterization of drug candidates to enhance efficacy and reduce late-stage attrition

  2024cites this paper
• Quantitative assessment of ligand BIAS from BIAS plots: The BIAS coefficient "kappa".

  2023cites this paper
• Community guidelines for GPCR ligand bias: IUPHAR review 32

  2022cites this paper
• Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties

  2021cites this paper
• Have Superagonist Properties Anti-CD40 Antibodies Fused to CD40 Ligand

  2021cites this paper
• Ligand bias in receptor tyrosine kinase signaling

  2020cites this paper
• Emergent Concepts of Receptor Pharmacology.

  2019cites this paper
• Biased Receptor Signaling in Drug Discovery

  2019cites this paper
• A Biased View of μ-Opioid Receptors?

  2019cites this paper
• Rat PHI, PHI-GLY and P H V ( l - 4 2) Stimulate Adenylate Cyclase in Six Rat Tissue and Cell Membranes

  2019cites this paper
• Antibody Structure and Function: The Basis for Engineering Therapeutics

  2019cites this paper
• Is the Quest for Signaling Bias Worth the Effort?

  2018cites this paper
• Biased Agonism in Drug Discovery—Is It Too Soon to Choose a Path?

  2018cites this paper
• Signaling bias in drug discovery

  2017cites this paper
• System-independent Scale of Agonism and Allosteric Modulation for Assessment of Selectivity , Bias and Receptor Mutation

  2017cites this paper
• A Scale of Agonism and Allosteric Modulation for Assessment of Selectivity, Bias, and Receptor Mutation

  2017cites this paper
• Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?

  2017cites this paper
• THROMBOXANE PROSTANOID RECEPTOR: FUNCTION, ACTIVATION AND POSSIBLE TARGET FOR CARDIOVASCULAR PROTECTION

  2017cites this paper
• Drug Affinity and Efficacy

  2017cites this paper
• Dysbindin‐1 modifies signaling and cellular localization of recombinant, human D3 and D2 receptors

  2016cites this paper
• Practical guide for calculating and representing biased signaling by GPCR ligands: A stepwise approach.

  2016cites this paper
• A Pluridimensional View of Biased Agonism

  2016cites this paper
• Measurement of Receptor Signaling Bias

  2016cites this paper
• The Effective Application of Biased Signaling to New Drug Discovery

  2015cites this paper
• New Lives for Seven Transmembrane Receptors as Drug Targets.

  2015cites this paper
• Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

  2015cites this paper
• Label-free functional selectivity assays.

  2015cites this paper
• Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors

  2015cites this paper
• What is pharmacological 'affinity'? Relevance to biased agonism and antagonism.

  2014cites this paper
• Quantifying biased β-arrestin signaling.

  2014cites this paper
• Emerging structural insights into biased GPCR signaling.

  2014cites this paper
• The Pharmacology of Functional, Biochemical, and Recombinant Receptor Systems

  2012cites this paper
• Multiple‐Targeting and Conformational Selection in the Estrogen Receptor: Computation and Experiment

  2011cites this paper
• The development of label-free cellular assays for drug discovery

  2011cites this paper
• Label-Free Receptor Assays.

  2011cites this paper
• Label-free receptor assays.

  2010cites this paper
• Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

  2010cites this paper
• Trace Amine-Associated Receptors as Emerging Therapeutic Targets

  2009cites this paper
• '7TM receptor allostery: putting numbers to shapeshifting proteins.

  2009cites this paper
• Interrogating 7TM receptors: Does texture in the question yield greater texture in the answer?

  2009cites this paper
• FLIPR assays of intracellular calcium in GPCR drug discovery.

  2009cites this paper
• Functional Selectivity: Theoretical Considerations and Future Directions

  2009cites this paper
• Trace amine-associated receptor 1 : a novel target of methamphetamine

  2008cites this paper
• 5-HT1A receptor-mediated apoptosis: death by JNK?

  2007cites this paper
• Trace Amine-Associated Receptor 1 Displays Species-Dependent Stereoselectivity for Isomers of Methamphetamine, Amphetamine, and Para-Hydroxyamphetamine

  2007cites this paper
• Some mechanistic insights into GPCR activation from detergent-solubilized ternary complexes on beads.

  2007cites this paper
• Porcine left atrial and sinoatrial 5‐HT4 receptor‐induced responses: fading of the response and influence of development

  2006cites this paper
• Agonist Concentration-response Models in Mouse and Rabbit Neocortex: Re-evaluation of Classical Models in Comparison with a Recently Developed General Response Function

  2005cites this paper
• G protein activation by G protein coupled receptors: ternary complex formation or catalyzed reaction?

  2004cites this paper
• Pharmacology of polymorphic variants of the human 5-HT1A receptor.

  2004cites this paper
• Structural and biological effects of a beta2- or beta3-amino acid insertion in a peptide.

  2003cites this paper
• Structural and biological effects of a β2‐ or β3‐amino acid insertion in a peptide

  2003cites this paper
• Modelling the consequences of receptor-G-protein promiscuity.

  2002cites this paper
• Mu and Delta opioid receptors activate the same G proteins in human neuroblastoma SH‐SY5Y cells

  2002cites this paper
• The assembly of recombinant signaling systems and their use in investigating signaling dynamics

  2000cites this paper
• The neural control of smooth muscle

  2000cites this paper
• Species-Dependent Pharmacological Properties of the Melanocortin-5 Receptor

  2000cites this paper
• Pharmacological properties of 5-Hydroxytryptamine(4) receptor antagonists on constitutively active wild-type and mutated receptors.

  2000cites this paper
• Endomorphin-1 and endomorphin-2 show differences in their activation of mu opioid receptor-regulated G proteins in supraspinal antinociception in mice.

  1999cites this paper
• Analysis of Apparent Noncompetitive Responses to Competitive H1-Histamine Receptor Antagonists in Fluorescent Imaging Plate Reader-Based Calcium Assays

  1999cites this paper
• Endomorphin-1 and Endomorphin-2 Show Differences in Their Activation of m Opioid Receptor-Regulated G Proteins in Supraspinal Antinociception in Mice 1

  1999cites this paper
• Influence of G protein type on agonist efficacy.

  1999cites this paper
• Analysis of asymmetry of agonist concentration-effect curves.

  1999cites this paper
• The recombinant 5‐HT1A receptor: G protein coupling and signalling pathways

  1999cites this paper
• Efficacy in drug receptor theory: outdated concept or under-valued tool?

  1999cites this paper
• Ligand-binding studies: old beliefs and new strategies.

  1998cites this paper
• Activation of Phospholipase A2 by the Nociceptin Receptor Expressed in Chinese Hamster Ovary Cells

  1998cites this paper
• The CGRP receptor can couple via pertussis toxin sensitive and insensitive G proteins

  1998cites this paper
• 5‐HT4 Receptors: Gene, Transduction and Effects on Olfactory Memory

  1998cites this paper
• Nociceptin receptor-mediated Ca2+ channel inhibition and its desensitization in NG108-15 cells.

  1998cites this paper
• Endothelin-1-induced alterations in phenylephrine-induced contractile responses are largely additive in physiologically diverse rabbit vasculature.

  1998cites this paper
• Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus.

  1998cites this paper
• Signal Transduction Correlates of Mu Opioid Agonist Intrinsic Efficacy: Receptor-Stimulated [S]GTPgS Binding in mMOR-CHO Cells and Rat Thalamus

  1998cites this paper
• Muscarinic M3 receptor coupling and regulation.

  1997cites this paper
• Regional Differences in Cannabinoid Receptor / G-protein Coupling in Rat Brain 1

  1997cites this paper
• Agonist Efficacy and Aliosteric Models of Receptor Action a

  1997cites this paper
• Regional differences in cannabinoid receptor/G-protein coupling in rat brain.

  1997cites this paper
• Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors.

  1996cites this paper
• Chronic treatment with antipsychotic drugs does not alter G protein alpha or beta subunit levels in rat brain.

  1996cites this paper
• The pharmacology of adenylyl cyclase modulation by GABAB receptors in rat brain slices.

  1996cites this paper
• The classification of seven transmembrane receptors in recombinant expression systems.

  1996cites this paper
• Thrombin inhibitors and thrombin receptor agonists/antagonists

  1996cites this paper
• Pharmacology of muscarinic acetylcholine receptor subtypes (m1-m5): high throughput assays in mammalian cells.

  1996cites this paper
• Regulation of dopamine D2 receptor affinity by cholecystokinin octapeptide in fibroblast cells cotransfected with human CCKB and D2L receptor cDNAs.

  1996cites this paper
• Mechanistic hypotheses for the activation of G-protein-coupled receptors.

  1996cites this paper
• Agonist potency at the cloned human beta-3 adrenoceptor depends on receptor expression level and nature of assay.

  1996cites this paper
• Functional partial agonism at cloned human muscarinic acetylcholine receptors.

  1996cites this paper
• TREATMENT DEVELOPMENT STRATEGIES FOR ALZHEIMER'S DISEASE

  1996cites this paper
• Characterization of cloned human dopamine D1 receptor-mediated calcium release in 293 cells.

  1995cites this paper
• On the importance of the "antagonist assumption" to how receptors express themselves.

  1995cites this paper
• Identification of residues involved in ligand binding to the neurokinin-2 receptor.

  1995cites this paper
• Agonist-receptor efficacy. II. Agonist trafficking of receptor signals.

  1995cites this paper
• Differences in agonist potency ratios at human m1 muscarinic receptors expressed in A9L and CHO cells.

  1995cites this paper
• Contractile actions of thrombin receptor‐derived polypeptides in human umbilical and placental vasculature: evidence for distinct receptor systems

  1995cites this paper
• Differential coupling of m1, m2 and m3 muscarinic receptor subtypes to inositol 1,4,5-trisphosphate and adenosine 3',5'-cyclic monophosphate accumulation in Chinese hamster ovary cells.

  1995cites this paper