Getting to the (right) surface

Cannabinoid receptors have a unique region that allows them to be sent to the appropriate location in a neuron.
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In neurons, cannabinoid type 1 receptors (in red) are not present on the surface of dendrites (in blue), but are present on the surface of axons (in yellow). Image credit: Fletcher-Jones et al., 2019 (CC BY 4.0)

The brain contains around 100 billion neurons that are in constant communication with one another. Each consists of a cell body, plus two components specialized for exchanging information. These are the axon, which delivers information, and the dendrites, which receive it. This exchange takes place at contact points between neurons called synapses. To send a message, a neuron releases chemicals called neurotransmitters from its axon terminals into the synapse. The neurotransmitters cross the synapse and bind to receptor proteins on the dendrites of another neuron. In doing so, they pass on the message.

Cannabinoid type 1 receptors (CB1Rs) help control the flow of information at synapses. They do this by binding neurotransmitters called endocannabinoids, which are unusual among neurotransmitters. Rather than sending messages from axons to dendrites, endocannabinoids send them in the opposite direction. Thus, it is dendrites that release endocannabinoids, which then bind to CB1Rs in axon terminals. This backwards, or 'retrograde', signalling dampens the release of other neurotransmitters. This slows down brain activity, and gives rise to the 'mellow' sensation that recreational cannabis users often describe.

Like most other proteins, CB1Rs are built inside the cell body. So, how do these receptors end up in the axon terminals where they are needed? Are they initially sent to both axons and dendrites, with the CB1Rs that travel to dendrites being rerouted back to axons? Or do the receptors travel directly to the axon itself? Fletcher-Jones et al. tracked newly made CB1Rs in rat neurons growing in a dish. The results revealed that the receptors go directly to the axon, before moving on to the axon terminals. A specific region of the CB1R protein is crucial for sending the receptors to the axon, and for ensuring that they do not get diverted to the dendrite surface. This region stabilizes CB1Rs at the axon surface, and helps to make the receptors available to bind endocannabinoids.

CB1Rs also respond to medical marijuana, a topic that continues to generate interest as well as controversy. Activating CB1Rs could help treat a wide range of diseases, such as chronic pain, epilepsy and multiple sclerosis. Future studies should build on our understanding of CB1Rs to explore and optimize new therapeutic approaches.