G-protein Receptor Kinase 5 Regulates the Cannabinoid Receptor 2-induced Up-regulation of Serotonin 2A Receptors

Abstract

We have recently reported that cannabinoid agonists can up-regulate and enhance the activity of serotonin 2A (5-HT 2A ) receptors in the prefrontal cortex (PFCx). Increased expression and activity of cortical 5-HT 2A receptors has been associated with neuropsychiatric disorders, such as anxiety and schizophrenia. Here we report that repeated CP55940 exposure selectively up-regulates GRK5 proteins in rat PFCx and in a neuronal cell culture model. We sought to examine the mechanism underlying the regulation of GRK5 and to identify the role of GRK5 in the cannabinoid agonist-induced up-regulation and enhanced activity of 5-HT 2A receptors. Interestingly, we found that cannabinoid agonist-induced up-regulation of GRK5 involves CB 2 receptors, β-arrestin 2, and ERK1/2 signaling because treatment with CB 2 shRNA lentiviral particles, β-arrestin 2 shRNA lentiviral particles, or ERK1/2 inhibitor prevented the cannabinoid agonist-induced up-regulation of GRK5. Most importantly, we found that GRK5 shRNA lentiviral particle treatment prevented the cannabinoid agonist-induced up-regulation and enhanced 5-HT 2A receptor-mediated calcium release. Repeated cannabinoid exposure was also associated with enhanced phosphorylation of CB 2 receptors and increased interaction between β-arrestin 2 and ERK1/2. These latter phenomena were also significantly inhibited by GRK5 shRNA lentiviral treatment. Our results suggest that sustained activation of CB 2 receptors, which up-regulates 5-HT 2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB 2 receptors; and the β-arrestin 2/ERK interactions. These data could provide a rationale for some of the adverse effects associated with repeated cannabinoid agonist exposure. Background: Cannabinoids regulate serotonin signaling in prefrontal cortex. Results: Cannabinoid-induced up-regulation and enhanced activity of serotonin 2A (5-HT 2A ) receptors are regulated by G-protein receptor kinase 5 (GRK5) in neuronal cells. Conclusion: Cannabinoids differentially regulate expression of GRKs, which could contribute to the modulation of CB 2 receptor signaling. Significance: Cannabinoid-induced up-regulation of 5-HT 2A receptors could represent an adverse effect of repeated exposure to cannabinoids.