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Related Concept Videos

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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Activation and Inactivation of G Proteins01:22

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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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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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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-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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Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
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Related Experiment Video

Updated: Jun 3, 2025

Rodent Brain Microinjection to Study Molecular Substrates of Motivated Behavior
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G protein Inactivation as a Mechanism for Addiction Treatment.

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This summary is machine-generated.

Nalfurafine and nalmefene, previously used in humans, can inactivate kappa opioid receptors (KORs) for extended periods. This KOR inactivation may offer new treatments for stress-related disorders like addiction and depression.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • The brain's dynorphin/kappa opioid receptor (KOR) system is implicated in stress-induced dysphoria.
  • KOR antagonists show therapeutic promise for addiction, depression, and psychosis.
  • Long-acting KOR antagonists like norBNI may function via cJun-kinase-mediated inactivation, not competitive inhibition.

Purpose of the Study:

  • To identify novel opioid ligands that induce norBNI-like KOR inactivation.
  • To investigate the potential therapeutic applications of these ligands.

Main Methods:

  • Screening of opioid ligands for KOR inactivation properties.
  • Assessment of KOR inactivation at doses significantly lower than those affecting mu opioid receptors.
  • Evaluation of nalfurafine and nalmefene in mouse models of fentanyl withdrawal and stress-induced aversion.

Main Results:

  • Nalfurafine (G-biased KOR agonist) and nalmefene (KOR partial agonist) were found to induce long-lasting KOR inactivation.
  • KOR inactivation occurred at 10-100 fold lower doses than mu opioid receptor effects for both ligands.
  • Daily microdosing with nalfurafine or nalmefene blocked KORs, mitigated stress-induced aversion, and reduced aversion during fentanyl withdrawal in mice.

Conclusions:

  • Nalfurafine and nalmefene can produce sustained KOR inactivation, similar to norBNI-like antagonists.
  • These ligands, with established human safety profiles, could be repurposed for treating dynorphin-mediated stress disorders.
  • The findings suggest a potential therapeutic strategy for addiction, depression, and psychosis by targeting KOR inactivation.