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Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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Drug-Receptor Interaction: Agonist01:25

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Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
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Transducer Mechanism: G Protein–Coupled Receptors01:30

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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GPCRs Regulate Adenylyl Cylase Activity01:09

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Updated: Mar 8, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Engineered Context-Sensitive Agonism: Tissue-Selective Drug Signaling through a G Protein-Coupled Receptor.

Wiebke K Seemann1, Daniela Wenzel1, Ramona Schrage1

  • 1Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).

The Journal of Pharmacology and Experimental Therapeutics
|January 14, 2017
PubMed
Summary
This summary is machine-generated.

Engineered context-sensitive agonism offers a novel postreceptor mechanism for achieving tissue-selective drug action. This approach, using dualsteric agonists, reduces unwanted cardiac side effects associated with acetylcholine M2-receptor activation.

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Area of Science:

  • Pharmacology
  • Drug Discovery
  • Molecular Biology

Background:

  • Drug discovery aims for selective ligands to target specific tissue functions.
  • Muscarinic agonists, like acetylcholine M2-receptor activators, can cause dangerous heart rate slowing, limiting their clinical use.

Purpose of the Study:

  • To introduce engineered context-sensitive agonism as a postreceptor mechanism for achieving tissue-selective drug action.
  • To investigate dualsteric agonists as a means to mitigate cardiac side effects of M2-receptor activation.

Main Methods:

  • Development and testing of dualsteric (orthosteric/allosteric) agonists.
  • Ex vivo and in vivo assessment of cardiac depression.
  • Utilizing cellular dynamic mass redistribution in living cells to explore underlying mechanisms.

Main Results:

  • Dualsteric agonists demonstrated reduced cardiac depression compared to conventional full agonists, both ex vivo and in vivo.
  • Context-sensitive agonism was identified as the mechanism, where agonists switch from full to partial agonism based on intracellular cAMP levels.
  • This mechanism functions even in target tissues utilizing the same pharmacologic receptor subtype.

Conclusions:

  • Engineered context-sensitive agonism provides a novel postreceptor strategy for achieving pharmacologic selectivity.
  • This approach holds promise for developing safer drugs with reduced side effects, particularly for G protein-coupled receptor targets.