The first thing many people think of when someone starts talking about cannabinoid signaling likely isn’t how cannabinoid exposure can change how your brain processes signals by directly modulating the number of receptors on neurons but likely has something to do with how recreational marijuana has been talked about in media or in pop culture. While there’s certainly nothing wrong with thinking of marijuana’s recreational uses first, cannabinoids do so much more for the human brain than create the ‘high’ associated with recreational marijuana use. Cannabinoids, a wide family of molecules, have been used to treat pain, muscle aches, anxiety, and even reduce the risks of addiction development when used in place of opiate pain medications. However, I’m most fascinated by how they directly change the number of receptors present on individual axons, leading to the formation of drug tolerance.
This is where beta-arrestin comes in. Let’s dive inside the brain.
Inside the brain: How beta-arrestin alters receptor concentration on post-synaptic neurons
Figure 1. Graphic showing GPCR activation and eventual endocytosis via beta-arrestin signaling. (Ma L, Pei G. 2007. β-arrestin signaling and regulation of transcription. Journal of Cell Science. doi:10.1242/jcs.03338.)
Let’s break it down. First, a ligand (a small signaling molecule) will bind to the GPCR on the extracellular (outside) part of the neuron. This is what tells the GPCR to activate. Once the ligand binds, the g protein dissociates from the GPCR and its alpha subunit, an effector protein, goes off to trigger the response. After the alpha subunit leaves the GPCR, GRK2 binds to the beta-gamma subunits of the GPCR and removes them, phosphorylating the GPCR’s tail in the process. This leaves the phosphorylated tail open for beta-arrestin to bind to it. Once beta-arrestin binds to the tail of the GPCR, it triggers endocytosis, bringing the entire GPCR into the cell in a small bubble of the cell membrane. This leads to desensitization by reducing the number of receptors available to respond to a given signal.
“That’s great,” you might say, “I now understand beta arrestin’s impacts on GPCRs, but how do endocannabinoids activate beta-arrestin?”
Great question. I’m glad you asked it. Let’s talk about it.
It’s actually pretty simple. Repeated exposure to cannabinoids that function as ligands for CB1 receptors increases GRK2 activity, thereby also increasing both beta-arrestin signaling, and GPCR endocytosis. This helps explain why some individuals who use cannabinoids repeatedly build up a tolerance, requiring more of the cannabinoid to achieve the same feeling. For example, THC, the cannabinoid found in recreational marijuana responsible for the “high” associated with its use, is likely the most well-known example of this effect.
Conclusion
In closing, there are two things I think you should take from this.
- Endocannabinoid signaling can be complicated. Beta arrestin’s role in changing receptor concentrations was only discovered in the last 20 years and its stimulation by endocannabinoids is still being understood.
- There’s still so much that science does not understand about how the brain works. It’s both a daunting and highly exciting prospect.
