The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation

Int J Neuropsychopharmacol. 2018 Dec 1;21(12):1102-1108. doi: 10.1093/ijnp/pyy059.

Abstract

Background: Previous evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D2 receptor, lacking ability both to activate and antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay.

Methods: We used G protein-coupled inward rectifier potassium channel activation in Xenopus oocytes to investigate UNC9994-induced modulation of G protein-dependent signaling at dopamine D2 receptor and dopamine D3 receptor.

Results: At dopamine D2 receptor, UNC9994 induced G protein-coupled inward rectifier potassium channel currents that were 15% of the maximal response to dopamine, with an EC50 of 185 nM. At dopamine D3 receptor, the ligand elicited 89% of the maximal dopamine response with an EC50 of 62 nM. Pertussis toxin abolished G protein-coupled inward rectifier potassium channel activation. Furthermore, UNC9994 antagonized dopamine-induced G protein-coupled inward rectifier potassium channel activation at dopamine D2 receptor.

Conclusions: UNC9994 modulates G protein-coupled inward rectifier potassium channel channel activation via pertussis toxin-sensitive G proteins at dopamine D2 receptor and dopamine D3 receptor. These findings may have implications for the interpretation of data obtained with this ligand.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / drug effects*
  • Humans
  • Ligands
  • Oocytes
  • Receptors, Dopamine D2*
  • Receptors, Dopamine D3
  • Signal Transduction / drug effects*
  • Xenopus laevis
  • beta-Arrestin 2*

Substances

  • Antipsychotic Agents
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Ligands
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • beta-Arrestin 2