Year: 2025
Type: article
Abstract: Cannabinoid type 1 receptors (CB 1 Rs) play important roles in regulating neurotransmitter release, synaptic plasticity, cell differentiation, and survival. CB 1 R is coupled via pertussis toxin (PTX)-sensitive Gαi/o proteins to the activation of extracellular regulated kinase (ERK) signaling. However, there are multiple Gαi/o isoforms, and it is unknown which of these isoforms is responsible for CB 1 R-induced phosphorylation of ERK. The purpose of this study was to determine which Gαi/o isoform(s) couple CB 1 R to ERK phosphorylation. HEK293 cells stably expressing the mouse CB 1 R (CB 1 R-HEK cells) were transfected with either pcDNA3.1 or pcDNA3.1 encoding PTX-insensitive mutants of Gαo, Gαi1, Gαi2, or Gαi3. PTX was used to inactivate endogenous Gαi/o isoforms before cells were treated with vehicle, delta-9-tetrahydrocannabinol (∆ 9 -THC), or CP55940 and ERK phosphorylation was measured by western blotting. CP55940 induced robust phosphorylation of ERK in cells transfected with vector alone. This effect was completely abolished by PTX treatment. CP55940-induced ERK phosphorylation was rescued by expression of PTX-insensitive forms of Gαo, Gαi1, Gαi2, or Gαi3, indicating that the CB1 receptor can couple to ERK phosphorylation through each of these Gαi/o isoforms. Consistent with its actions as a partial agonist, ∆ 9 -THC induced nominal (two to four-fold) increases in ERK phosphorylation that did not reach statistical significance except in cells transfected with PTX-insensitive Gαi3. These data demonstrate that CB 1 R can couple to ERK phosphorylation through Gαo, Gαi1, Gαi2, or Gαi3 when stimulated with CP55940 (full agonist). However, ∆ 9 -THC (partial agonist)-induced ERK activation might require high levels of Gαi3 expression.
Source: Neuroreport
Authors: Boyd R. Rorabaugh, Daniel J. Morgan
Institution: Marshall University
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institute on Drug Abuse
OpenAlex ID: W4407785600