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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.
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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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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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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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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G-protein Coupled Receptors01:21

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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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G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

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GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
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Intracellular GPCR modulators enable precision pharmacology.

Brian E Krumm1, Bryan L Roth1,2

  • 1Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.

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|May 15, 2025
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Summary

Biased signaling in G-protein-coupled receptors (GPCRs) uses intracellular modulators to fine-tune drug responses. This approach offers potential for precision pharmacology in Rhodopsin-Like GPCRs.

Keywords:
PharmacogeneticsReceptor pharmacology

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • G-protein-coupled receptors (GPCRs) are key drug targets but complex signaling pathways hinder development.
  • Intracellular ligand binding sites offer new avenues for modulating GPCR activity.
  • Pathway-biased signaling presents an opportunity for targeted therapeutic interventions.

Purpose of the Study:

  • To explore biased signaling mechanisms in GPCRs.
  • To investigate the role of intracellular modulators in GPCR drug discovery.
  • To understand the application of biased signaling for precision pharmacology in Class A GPCRs.

Main Methods:

  • Literature review on biased signaling and intracellular GPCR modulators.
  • Analysis of signaling pathways for Class A (Rhodopsin-Like) GPCRs.
  • Conceptual framework for precision pharmacology using biased ligands.

Main Results:

  • Identified intracellular binding sites that promote pathway-biased signaling.
  • Demonstrated cooperation between orthosteric and allosteric ligands for biased responses.
  • Highlighted the potential of biased signaling for selective pathway activation.

Conclusions:

  • Biased signaling and intracellular modulators are crucial for precision pharmacology.
  • Targeting intracellular sites offers enhanced control over GPCR signal transduction.
  • This strategy holds promise for developing more effective and safer therapeutics for Rhodopsin-Like GPCRs.