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VAMP2: a crucial player in the delivery of MOR to the synapse

Transporting Protein-coupled receptors (GPCRs) to the synapse, where they are involved in neurotransmission, is a complex process involving several steps. From a general overview, after GPCRs synthesis in the endoplasmic reticulum, GPCRs are transported to the Golgi apparatus to undergo additional post-translational modifications and sorted for transport to their final destination. Several molecules from the SNARE complex, including vesicle-associated membrane protein 2 (VAMP2), regulate this last step toward the cell membrane [5,7].

VAMP2, also known as synaptobrevin, is a type of SNARE protein found on the synaptic vesicle membrane in neurons and is responsible for binding to the t-SNARE complex, a group of proteins found on the target membrane of the synapse. The t-SNARE complex is composed of two different proteins: syntaxin and SNAP-25; syntaxin is found on the target membrane of the synapse, while SNAP-25 is present on the membrane of the presynaptic neuron. The t-SNARE complex and VAMP2 interact to form the SNARE complex, which is essential for the fusion of the synaptic vesicle membrane with the target membrane, resulting in the release of neurotransmitters into the synapse. However, although the function of the SNARE protein complex in neurotransmitter release has been well characterized, the mechanisms that modulate the delivery of GPCRs to the membrane cell still need to be well known [3-5].

In the context of GPCR recycling, this process is complex and highly regulated that involves multiple molecular players, including SNARE proteins; here, SNARE proteins play a role in the fusion of recycling endosomes with the plasma membrane. Some studies have suggested that VAMP2 may be involved in regulating dopamine D2 receptor signaling by controlling the trafficking of the receptor to the cell surface. In addition, VAMP2 can interact with other GPCRs, such as the beta-2 adrenergic receptor and the mu-opioid receptor (MOR) [1,6,7]. However, the selectivity of SNARE complex proteins to regulate the release of different types of GPCRs during recycling is one of the questions still under investigation in the field.

Through developing a high-resolution method, Hao Chen et al. directly visualized the fusion of vesicles containing GPCRs to the plasma membrane. With this technology, they evidenced the presence of VAMP2, specifically in recycling vesicles containing MOR but not B2AR or TFR in HEK293 cells and primary neurons.

This study supports the idea that proteins from the fusion machinery are specific about the cargo molecules within the vesicles. These data are fascinating because in the case of MOR, which is a receptor with several splicing variants, its traffic to the membrane can be modified depending on the integrity of its bi-leucine sequence (which is considered a key element in its recycling), which can interact with different fusion proteins and also this different molecular codes will be modulated by different opioids, either endogenous or exogenous, promoving a differential organization of MOR receptors in vesicles with different proteins of the fusion machinery [6].

Since MOR receptor regulates pain perception and reward, the dysfunction in the MOR-SNARE complex interaction can lead to various neurological disorders, such as chronic pain and addiction. Therefore, their comprehension is essential for developing new treatments for these disorders and advancing our understanding of the brain and nervous system. You can consult the article at the following link:

#GPCR #DrGPCR#Ecosystem

  1. Crilly, S.E., W. Ko, Z.Y. Weinberg, and M.A. Puthenveedu. 2021. Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist. Elife. 10:e67478.

  2. Drake, M.T., S.K. Shenoy, and R.J. Lefkowitz. 2006. Trafficking of G protein coupled receptors. Circ. Res. 99:570–582.

  3. Jurado, S., D. Goswami, Y. Zhang, A.J.M. Molina, T.C. Südhof, and R.C. Malenka. 2013. LTP requires a unique postsynaptic SNARE fusion machinery. Neuron. 77:542–558.

  4. Schoch, S., F. Deak, A. K ´ onigstorfer, M. Mozhayeva, Y. Sara, T.C. Südhof, and ¨ E.T. Kavalali. 2001. SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science. 294:1117–1122.

  5. 5. Neurotransmitter release: The last millisecond in the life of a synaptic vesicle. Neuron. 80:675–690.

  6. Wang, F., X. Chen, X. Zhang, and L. Ma. 2008. Phosphorylation state of muopioid receptor determines the alternative recycling of receptor via Rab4 or Rab11 pathway. Mol. Endocrinol. 22:1881–1892.

  7. Wickner, W., and R. Schekman. 2008. Membrane fusion. Nat. Struct. Mol. Biol. 15:658–664.

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