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Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

13.7K
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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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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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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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,...
2.6K
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

6.0K
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...
6.0K
GPCR Desensitization01:12

GPCR Desensitization

6.6K
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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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding

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Hydration-mediated G-protein-coupled receptor activation.

Steven D E Fried1, Kushani S K Hewage1, Anna R Eitel1

  • 1Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721.

Proceedings of the National Academy of Sciences of the United States of America
|May 18, 2022
PubMed
Summary

Rhodopsin activation involves significant water movement into the protein, challenging previous assumptions about G-protein coupled receptors (GPCRs). This discovery highlights the crucial role of bulk water in GPCR signaling mechanisms.

Keywords:
GPCRosmotic stressrhodopsinsponge modelstructural water

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Biophysics

Background:

  • G-protein coupled receptors (GPCRs), including rhodopsin, are crucial drug targets.
  • The role of structural water in GPCR activation and signaling remains poorly understood.

Purpose of the Study:

  • To investigate the physiological relevance of water movement during rhodopsin activation.
  • To quantify hydration changes associated with rhodopsin signaling in lipid membranes.

Main Methods:

  • Utilized osmotic stress with polyethylene glycol (PEG) osmolytes to measure metarhodopsin equilibrium shifts.
  • Quantified reversible hydration changes in response to varying osmolyte sizes.

Main Results:

  • Light activation of rhodopsin is coupled to a substantial influx of bulk water (80-100 molecules).
  • Osmolyte size directly modulates rhodopsin activation, with smaller molecules favoring activation and larger ones favoring the inactive state.
  • Observed a universal response to osmotic stress, suggesting a dynamic, hydrated state upon photoactivation.

Conclusions:

  • Bulk water influx is essential for establishing the active conformation of GPCRs, not just bound water.
  • Rethinking the role of water dynamics in the GPCR energy landscape is necessary.
  • This finding provides new insights into GPCR activation mechanisms and potential drug development targets.