Abstract
We have recently reported that cannabinoid agonists can up-regulate and enhance the activity of serotonin 2A (5-HT2A) receptors in the prefrontal cortex (PFCx). Increased expression and activity of cortical 5-HT2A 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-HT2A receptors. Interestingly, we found that cannabinoid agonist-induced up-regulation of GRK5 involves CB2 receptors, β-arrestin 2, and ERK1/2 signaling because treatment with CB2 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-HT2A receptor-mediated calcium release. Repeated cannabinoid exposure was also associated with enhanced phosphorylation of CB2 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 CB2 receptors, which up-regulates 5-HT2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB2 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.
Highlights
Cannabinoids regulate serotonin signaling in prefrontal cortex
We initially examined the effect of repeated exposure to CP55940 (CB1/CB2 receptor agonist) on the phosphorylation status of the CB2 receptors in rat prefrontal cortex (PFCx) (Fig. 1A)
Because CP55940-enhanced expression of selective G-protein receptor kinases (GRKs) could underlie the increased phosphorylation of CB2 receptor, we studied the effect of CP55940 exposure on the protein levels of G-protein receptor kinase 5 (GRK5), GRK6, and GRK2 proteins in rat PFCx
Summary
Cannabinoids regulate serotonin signaling in prefrontal cortex. Results: Cannabinoid-induced up-regulation and enhanced activity of serotonin 2A (5-HT2A) receptors are regulated by G-protein receptor kinase 5 (GRK5) in neuronal cells. Our results suggest that sustained activation of CB2 receptors, which up-regulates 5-HT2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB2 receptors; and the -arrestin 2/ERK interactions These data could provide a rationale for some of the adverse effects associated with repeated cannabinoid agonist exposure. Activity of 5-HT2A2 receptors in rat prefrontal cortex (PFCx) and in two neuronal cell models [1,2,3,4] This cannabinoid-mediated up-regulation of 5-HT2A receptors was 1) induced by nonselective CB1/CB2 and selective CB2 receptor agonists [2, 4] and 2) inhibited by selective CB2, but not CB1, shRNA lentiviral particles, suggesting that CB2 receptors mediate this phenomenon [3].
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