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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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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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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 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 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 Inactivation as a Mechanism for Addiction Treatment.

Carlie Neiswanger1, Micaela V Ruiz1, Kandace Kimball1

  • 1Department of Pharmacology, University of Washington, Seattle, Washington.

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Summary
This summary is machine-generated.

Nalfurafine and nalmefene cause long-lasting kappa opioid receptor (KOR) inactivation, offering potential treatments for stress-related disorders. This KOR inactivation mechanism, distinct from competitive inhibition, shows therapeutic promise for conditions like addiction and depression.

Keywords:
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Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • The endogenous dynorphin/kappa opioid receptor (KOR) system mediates stress-induced dysphoria.
  • KOR antagonists are potential therapeutics for addiction, depression, and psychosis.
  • Long-acting norbinaltorphimine (norBNI)-like antagonists may inactivate KORs via a c-Jun-kinase mechanism.

Purpose of the Study:

  • To screen for opioid ligands that induce norbinaltorphimine (norBNI)-like kappa opioid receptor (KOR) inactivation.
  • To investigate the therapeutic potential of KOR inactivation for dynorphin-mediated stress disorders.

Main Methods:

  • Screening of opioid ligands for KOR inactivation.
  • Assessment of nalfurafine and nalmefene for KOR inactivation.
  • Evaluation of KOR inactivation sex dependency and hormonal influences.
  • Dose-response studies for KOR inactivation versus mu opioid receptor actions.
  • Investigation of KOR inactivation effects on various physiological responses in mice.

Main Results:

  • Nalfurafine and nalmefene induce long-lasting KOR inactivation at lower doses than required for mu opioid receptor effects.
  • KOR inactivation by nalfurafine is sex-dependent, occurring during estrus or after progesterone treatment.
  • Daily microdosing of nalfurafine or nalmefene accumulates inhibition, blocking KORs involved in antinociception, stress aversion, and dysphoria during opioid withdrawal.
  • KORs mediating diuretic and antipruritic effects are not regulated by JNK.

Conclusions:

  • Nalfurafine and nalmefene demonstrate a novel mechanism of KOR inactivation.
  • These drugs, with established safety profiles, could be repurposed for treating dynorphin-mediated stress disorders.
  • The findings suggest a new therapeutic avenue for addiction, depression, and psychosis.