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Related Concept Videos

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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G Protein-coupled Receptors01:15

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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 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

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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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Variability: Analysis01:11

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Measures of variability are statistical metrics that reveal the dispersion pattern within a dataset. They are pivotal in biostatistics, providing insights into the heterogeneity within health and biological data. Variability signifies the degree to which data points diverge from one another, helping researchers understand the potential range of values and associated uncertainty within the data.
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Random Variables01:09

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A random variable is a single numerical value that indicates the outcome of a procedure. The concept of random variables is fundamental to the probability theory and was introduced by a Russian mathematician, Pafnuty Chebyshev, in the mid-nineteenth century.
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Related Experiment Video

Updated: Jan 24, 2026

G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay
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Variable G protein determinants of GPCR coupling selectivity.

Najeah Okashah1, Qingwen Wan1, Soumadwip Ghosh2

  • 1Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912.

Proceedings of the National Academy of Sciences of the United States of America
|May 31, 2019
PubMed
Summary
This summary is machine-generated.

G protein-coupled receptors (GPCRs) activate G proteins, but selectivity mechanisms remain unclear. This study reveals the Gα subunit core is as crucial as its C terminus for selective GPCR coupling, challenging prior assumptions.

Keywords:
G protein selectivityG protein-coupled receptorGPCRternary complex

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Area of Science:

  • Cellular Biology
  • Molecular Pharmacology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) initiate cellular signaling by activating specific heterotrimeric G proteins.
  • The precise mechanisms governing GPCR-G protein coupling selectivity are not fully understood.
  • The C-terminal region of the Gα subunit is traditionally considered the primary determinant for receptor recognition.

Purpose of the Study:

  • To directly assess the coupling selectivity between various GPCRs and Gα subunits.
  • To investigate the relative contributions of the Gα subunit C terminus and core to coupling specificity.
  • To elucidate general principles governing GPCR-G protein interactions.

Main Methods:

  • Utilized a sensitive bioluminescence resonance energy transfer (BRET) assay for direct coupling measurements.
  • Employed a panel of 14 representative GPCRs and 16 Gα subunits, including wild-type and chimeric constructs.
  • Controlled for both ligand and nucleotide binding states within the BRET assay.

Main Results:

  • GPCRs coupled to Gs and Gq showed promiscuous coupling to Gi1 heterotrimers, while Gi-coupled receptors exhibited higher selectivity.
  • Gα subunit chimeras demonstrated that the C terminus is important but not solely determinant for selectivity.
  • The Gα subunit core significantly influences coupling selectivity, sometimes more than the C terminus, with variable importance across receptors.

Conclusions:

  • The Gα subunit core plays a critical role in GPCR coupling selectivity, comparable to or exceeding the C terminus.
  • GPCR-G protein coupling selectivity is determined by a complex interplay between the Gα subunit core and C terminus.
  • The critical determinants of selectivity vary significantly, even for receptors coupling to the same G protein family.