WIN55,212-2, A Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

• Main Authors: Dongchen An, Steve Peigneur, Jan Tytgat
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Biomedicines
• Subjects: dual modulation; WIN55,212-2; cannabinoid receptor type 1 (CB1) and type 2 (CB2); G protein-coupled inward rectifier potassium channels 1 (GIRK1) and 2 (GIRK2)
• Online Access: https://www.mdpi.com/2227-9059/9/5/484

The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a <i>Xenopus laevis</i> oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2- GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.