Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function

Area of Science:

• Pharmacology
• Neuroscience
• Molecular Biology

Background:

• G-protein-coupled receptor (GPCR) signaling exhibits functional selectivity.
• Arrestins mediate GPCR functional selectivity through ligand-specific recruitment.

Purpose of the Study:

• To investigate agonist-selective arrestin isoform recruitment to the delta opioid receptor (DOR).
• To elucidate the role of different arrestin isoforms in DOR signaling and behavioral responses.

Main Methods:

• Utilized mouse models with knock-outs (KOs) for arrestin 2 and arrestin 3.
• Administered various DOR agonists (SNC80, ARM390, JNJ20788560) to assess behavioral effects.
• Performed live-cell imaging in HEK293 cells to visualize receptor-arrestin interactions.
• Examined DOR-Ca(2+) channel coupling in dorsal root ganglia.

Main Results:

• High-internalizing agonist SNC80 preferentially recruited arrestin 2, enhancing its efficacy in arrestin 2 KOs.
• Low-internalizing agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3.
• Arrestin 3 KOs exhibited acute tolerance and impaired resensitization to low-internalizing agonists.
• DORs form pre-engaged complexes with arrestin 3 at the membrane, strengthened by ARM390.

Conclusions:

• Delta opioid receptor agonists differentially recruit arrestin isoforms, mediating ligand bias.
• Arrestin 3 plays a novel role in facilitating receptor resensitization and inhibiting tolerance.
• Agonist-specific arrestin recruitment dictates distinct downstream signaling events and functional outcomes.