• Home
  • Search Results
  • Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes.

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes.

Biochemical pharmacology (2018-09-09)
Gemma Navarro, Irene Reyes-Resina, Rafael Rivas-Santisteban, Verónica Sánchez de Medina, Paula Morales, Salvatore Casano, Carlos Ferreiro-Vera, Alejandro Lillo, David Aguinaga, Nadine Jagerovic, Xavier Nadal, Rafael Franco
ABSTRACT

Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2, or CB1-CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (Δ9-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CB1R and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the Gi protein coupled to CB2R. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC50/EC50 values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Duolink® In Situ Red Starter Kit Mouse/Rabbit
Sigma-Aldrich
Duolink® In Situ PLA® Probe Anti-Rabbit PLUS, Affinity purified Donkey anti-Rabbit IgG (H+L)
Sigma-Aldrich
Duolink® In Situ PLA® Probe Anti-Mouse MINUS, Affinity purified Donkey anti-Mouse IgG (H+L)
Sigma-Aldrich
Duolink® In Situ Detection Reagents Red
Sigma-Aldrich
Duolink® In Situ Orange Starter Kit Mouse/Rabbit
Sigma-Aldrich
Duolink® In Situ Wash Buffers, Fluorescence
Sigma-Aldrich
Duolink® In Situ Detection Reagents Orange
Sigma-Aldrich
Duolink® In Situ PLA® Probe Anti-Rabbit MINUS
Sigma-Aldrich
Duolink® In Situ PLA® Probe Anti-Mouse PLUS
Sigma-Aldrich
Duolink® In Situ Detection Reagents Green
Sigma-Aldrich
Duolink® In Situ Mounting Medium with DAPI
Sigma-Aldrich
Duolink® In Situ Detection Reagents FarRed
Sigma-Aldrich
Duolink® In Situ Probemaker MINUS
Sigma-Aldrich
Duolink® In Situ Probemaker PLUS
Sigma-Aldrich
Duolink® In Situ Detection Reagents Brightfield
Sigma-Aldrich
Duolink® In Situ PLA® Probe Anti-Goat MINUS, Affinity purified Donkey anti-Goat IgG (H+L)
Sigma-Aldrich
Duolink® flowPLA Detection Kit - FarRed, Duolink® PLA kit for Flow Cytometry with FarRed Detection
Sigma-Aldrich
Duolink® PLA Control Kit - PPI, Control Kit to reliably detect Protein-Protein Interactions (PPI) with Duolink® PLA
Sigma-Aldrich
Duolink® In Situ PLA® Probe Anti-Goat PLUS
Sigma-Aldrich
Duolink® flowPLA Detection Kit - Green, Duolink® PLA kit for Flow Cytometry with Green Detection
Sigma-Aldrich
Duolink® flowPLA Detection Kit - Red, DUOLINK® : PLA kit for Flow Cytometry with Red Detection
Sigma-Aldrich
Duolink® In Situ Wash Buffer, Brightfield
Sigma-Aldrich
Duolink® In Situ Red Starter Kit Goat/Rabbit
Sigma-Aldrich
Duolink® In Situ Microplate Nuclear Stain, Anti-Fade
Sigma-Aldrich
Duolink® In Situ Orange Starter Kit Goat/Rabbit
Sigma-Aldrich
Duolink® flowPLA Detection Kit - Orange, Duolink® PLA kit for Flow Cytometry with Orange Detection
Sigma-Aldrich
Duolink® In Situ Red Starter Kit Mouse/Goat
Sigma-Aldrich
Duolink® In Situ Microplate Heat Transfer Block
Sigma-Aldrich
Duolink® In Situ Orange Starter Kit Mouse/Goat