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GPCR Desensitization01:12

GPCR Desensitization

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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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Drug Discovery: Overview01:26

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Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
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Aggregates Classification01:29

Aggregates Classification

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Aggregate classification is generally based on its size, petrographic characteristics, weight, and source. Size classification ranges from coarse to fine aggregates, defined by the size of the particles. Coarse aggregates are particles that do not pass through ASTM sieve No. 4, and aggregates that pass through the sieve are fine aggregates.
Petrographic classification groups aggregates based on common mineralogical characteristics. Some of the common mineral groups found in aggregates are...
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Bonding and Strength of Aggregate01:12

Bonding and Strength of Aggregate

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The bond between aggregate particles and the cement matrix is significantly influenced by the shape and surface texture of the aggregates. High-strength concretes benefit from a rougher texture, which leads to stronger bonding due to greater adhesion. Angular aggregates with larger surface areas also enhance this bond. The bonding quality, however, is complex to assess as no universally accepted test exists. Good bonding is indicated when a crushed concrete specimen shows some aggregate...
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Specific Gravity of Aggregate01:19

Specific Gravity of Aggregate

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Aggregates typically contain pores, which can be either permeable or impermeable. Considering the pores in the aggregates, the specific gravity of aggregates is defined in three different forms, namely, bulk or gross specific gravity, apparent specific gravity, and absolute specific gravity.
Bulk or gross specific gravity is calculated by taking the ratio of the mass of aggregates in the saturated surface-dry state to the total volume that includes both the solids and the voids within the...
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Bulk Density of Aggregate01:22

Bulk Density of Aggregate

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Bulk density refers to the mass of aggregate particles that would fill a unit volume. The concept of bulk density originates from the inability to pack aggregate particles in a manner that completely eliminates void spaces. Hence, the term bulk refers to the volume that encompasses both the aggregates and the voids. This measurement is crucial when aggregates are batched by volume and is used to convert quantities by mass to volume.
Most natural mineral aggregates, like sand and gravel,...
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Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
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Discovery of Pathologic GPCR Aggregation.

Ursula Quitterer1,2, Said AbdAlla1

  • 1Molecular Pharmacology, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.

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|February 15, 2019
PubMed
Summary

G-protein-coupled receptors (GPCRs) can form abnormal aggregates, impacting signaling and disease. Discovering these pathologic GPCR aggregates reveals new therapeutic targets for conditions like hypertension and neurodegeneration.

Keywords:
Alzheimer's diseaseG-protein-coupled receptoratherosclerosisbeta-arrestinbiased agonistneurodegenerationoligomerizationpreeclampsia

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cellular Signaling

Background:

  • G-protein-coupled receptors (GPCRs) are crucial drug targets, traditionally viewed as monomers.
  • This contrasts with other membrane receptors known to signal via dimeric complexes.
  • Recent evidence highlights GPCR aggregation into dimers and oligomers, forming homomeric and heteromeric complexes.

Purpose of the Study:

  • To investigate the role of GPCR aggregation in cellular signaling and disease.
  • To identify and characterize pathologic GPCR aggregates.
  • To explore GPCR aggregation as a novel therapeutic target.

Main Methods:

  • Investigated GPCR aggregation mechanisms.
  • Discovered and characterized the AT1-B2 heteromer.
  • Analyzed the role of GPCR aggregates in various diseases.

Main Results:

  • Identified the first pathologic GPCR aggregation: angiotensin II AT1 receptor and bradykinin B2 receptor heteromerization.
  • Demonstrated that increased AT1-B2 heteromerization causes angiotensin II hypersensitivity in preeclampsia.
  • Found other pathologic GPCR aggregates implicated in atherosclerosis, neurodegeneration, and Alzheimer's disease.

Conclusions:

  • GPCR aggregation is a significant factor in receptor function and signaling.
  • Pathologic GPCR aggregation is an independent, disease-specific process.
  • GPCR aggregates represent a novel and promising target for pharmacologic interventions.