Synucleins are a group of three proteins abundant in the brain that cause Parkinson’s Disease. In contrast, they prevent neurodegeneration, but we know little about their stunning beneficial function. But as an update to old textbooks, a new study found that synucleins release endocannabinoids from neurons, which allows them to travel in reverse across terminals and park inside CB1 receptors.
Demand is a well-known but often overlooked mechanism of the endocannabinoid system. Animals that contain a backbone, vertebrates, possess endocannabinoid systems comprised of various neurotransmitters and receptors. Endocannabinoids maintain balance throughout a living organism, a state known as homeostasis. And calcium ions facilitate numerous muscle and nerve functions, but they also demand neurons to release endocannabinoids. And it turns out that calcium is not alone in this role, according to new research from Standford University and Peking University published in Nature Neuroscience.
How do CB1 receptors catch ligands?
Cannabinoid receptors make their home in one end of a neuron — known as a terminal. And CB1 receptors, which catch the cannabis ingredient called THC accept two primary transmitters known as 2-AG and anandamide. The terminal is one-half of a synapse or a connection between two cells. Two terminals contain synthesis and metabolic machinery for the endocannabinoids 2-AG and anandamide, respectively. Research from the late 1990s found that 2-AG production occurs in the post-synaptic terminal before previously unknown mechanisms carried it to the pre-synapse on the other side.
An electrical action within the cell drives endocannabinoid transportation, which is where calcium ions take their role. Opposing 2-AG synthesis, enzymes inside the pre-terminal produce anandamide before calcium ions push it across the neuron. But new research found that postsynaptic endocannabinoid release further requires synuclein, the same protein responsible for Parkinson’s Disease.
Synuclein and endocannabinoid plasticity
Two mechanisms of endocannabinoid plasticity in separate regions of the brain — striatum and hippocampus — were severely disrupted in mice without synuclein. Endocannabinoid plasticity defines the system’s flexibility and ability to respond to the body’s constantly shifting demands. Yet, CB1 receptors, which reside in the preterminal, function normally in mice bred without synuclein proteins.
Essentially, CB1 receptor activity occurred when researchers introduced endocannabinoids into the post-terminal in normal mice. But the receptors, despite their normal function, failed to react to post-synaptic endocannabinoids in mice bred without synuclein. This result indicates that, in different regions of the brain, calcium current and synuclein release the two primary endocannabinoids from post to presynapse, a normal means of travel for 2-AG. And out of the three proteins, endocannabinoid release requires either gamma and beta together or alpha-synuclein by itself.
The researchers concluded that,
'Given that our results also reveal that eCBs are likely released via a synuclein-dependent postsynaptic membrane mechanism, they reconcile two open questions in neuroscience—namely, how eCBs are released and for what functions synucleins are essential— thereby forming the basis for further insights into the modulatory mechanisms that control neural circuits in healthy and neurodegenerative brains.'
Previously, this author elucidated indirect disruptions in endocannabinoid transportation and cannabinoid receptor recycling by alpha-synuclein. But the new research provides evidence that synuclein directly drives endocannabinoid release from the post-synapse to the CB1 receptor housed in the terminal on the other adjacent neuron.
Source
Albarran, E., Sun, Y., Liu, Y. et al. Postsynaptic synucleins mediate endocannabinoid signaling. Nat Neurosci (2023).
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