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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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GPCR Desensitization01:12

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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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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.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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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.
GPCRs are also called heptahelical,...
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Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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G-protein Coupled Receptors01:21

G-protein Coupled Receptors

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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Related Experiment Video

Updated: Jan 11, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Elucidating biased signaling in class A GPCRs.

Ningyang Xu1, Edwin Legall1, Roger H Johnson2

  • 1Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Trends in Pharmacological Sciences
|November 8, 2025
PubMed
Summary

Biased signaling in G protein-coupled receptors (GPCRs) allows drugs to target specific pathways, potentially reducing side effects. Understanding the structural basis of this bias is key for developing more effective therapeutics.

Keywords:
G protein–coupled receptors (GPCRs)NanoLuc Binary Technology (NanoBiT)biased signalingbioluminescence resonance energy transfer (BRET)cryo–electron microscopy (cryo-EM)structure-based drug design (SBDD)

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Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
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Area of Science:

  • Pharmacology
  • Structural Biology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets, mediating numerous physiological processes.
  • Biased signaling, where ligands selectively activate G proteins or β-arrestins, presents an opportunity for developing therapeutics with improved safety profiles.
  • The structural mechanisms underlying biased signaling in Class A GPCRs remain largely undefined.

Purpose of the Study:

  • To review the key mechanisms driving biased signaling in GPCRs.
  • To integrate structural and functional data to understand ligand-induced conformational changes.
  • To provide a mechanistic framework for developing pathway-selective GPCR therapeutics.

Main Methods:

  • Utilizing cryo-electron microscopy (cryo-EM) to determine receptor structures.
  • Employing real-time functional assays like bioluminescence resonance energy transfer (BRET) and NanoLuc Binary Technology (NanoBRET).
  • Integrating structural and functional data to map signaling pathways.

Main Results:

  • Distinct ligand binding modes induce specific receptor conformations.
  • These conformations dictate the engagement of downstream signaling partners (G proteins or β-arrestins).
  • Key mechanisms include microswitch transitions, intracellular interface remodeling, and allosteric modulation.

Conclusions:

  • Understanding GPCR structural dynamics is crucial for biased ligand design.
  • This knowledge facilitates the development of isoform- and tissue-specific therapeutics.
  • Pathway-selective GPCR targeting offers improved efficacy and reduced off-target effects.