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Related Concept Videos

GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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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 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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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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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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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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Related Experiment Video

Updated: Jan 15, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Biased Allosteric Modulation in GPCR Drug Discovery.

Jingzhi-Christina Zhou1,2, Michelle Z Li2,3, Alan Long2,4

  • 1Department of Chemistry, Duke University, Durham, NC, USA.

Handbook of Experimental Pharmacology
|October 7, 2025
PubMed
Summary

Allosteric modulators offer precise control over G protein-coupled receptors (GPCRs) signaling, enhancing drug discovery by reducing side effects. Biased allosteric modulators (BAMs) represent a promising strategy for developing targeted therapeutics.

Keywords:
Allosteric modulationDrug discoveryFunctional selectivityG protein-coupled receptor (GPCR)Signaling biasTherapeutic development

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Area of Science:

  • Pharmacology
  • Drug Discovery
  • Molecular Biology

Background:

  • Orthosteric drugs targeting G protein-coupled receptors (GPCRs) often lack subtype specificity and cause side effects.
  • Allosteric modulators (AMs) bind to distinct sites, offering improved selectivity and pathway bias.
  • Biased signaling and allosteric modulation represent a paradigm shift in GPCR drug discovery.

Purpose of the Study:

  • To review the principles of biased signaling and allosteric modulation in GPCRs.
  • To highlight strategies for designing biased allosteric modulators (BAMs).
  • To explore the potential of BAMs for developing precision therapeutics.

Main Methods:

  • Review of recent structural and biophysical studies on GPCR allosteric modulation.
  • Analysis of biased signaling pathways involving G proteins and β-arrestins.
  • Discussion of ligand design strategies for BAMs.

Main Results:

  • Allosteric modulation allows fine-tuning of GPCR conformation and transducer engagement.
  • AMs can preferentially direct signaling toward specific pathways (G protein or β-arrestin).
  • Biased allosteric modulators (BAMs) selectively tune GPCR responses.

Conclusions:

  • Allosteric modulation offers enhanced subtype selectivity and pathway bias compared to orthosteric approaches.
  • BAMs hold significant promise for developing targeted GPCR therapies with improved efficacy and safety profiles.
  • The convergence of biased signaling and allosteric modulation is revolutionizing GPCR drug discovery.