Neurexins

What are Neurexins?

Neurexins are defined as a group of transmembrane molecules or cell adhesion proteins that are widely expressed in neurons, particularly on presynaptic membranes, playing an essential role in neuron connection at the synapse. By interaction with their binding partners' postsynaptic neuroligins, neurexins exhibit significant roles in the formation of synapses and signal transduction, being recognized as a key component of neural networks. Mutations in human neurexin genes can cause several psychiatric and neurological diseases, such as autism spectrum disorders, cognitive dysfunctions, schizophrenia, and Tourette syndrome.

Neurexin Structure Features

Currently, 3 neurexin members encoded by paralogous genes (NRXN1, NRXN2, and NRXN3) have been discovered and identified in mammals. Human neurexin has 2 isoforms, α-neurexin and β-neurexin, which is controlled by two distinct promoters, an upstream promoter for α-neurexin expression and a downstream promoter for β-neurexin expression. α-neurexins are larger than β-neurexins, which are transmembrane proteins sharing identical intracellular domains and transmembrane regions. The extracellular part of longer α-neurexins contains 6 laminin neurexin sex hormone-binding globulin (LNS) domains with 3 epidermal growth factor (EGF)-like domains interspersed in, whereas β-neurexins only contain an LNS domain. All α-neurexins and β-neurexins have an O-linked carbohydrate-rich stalk at the proximal membrane in the extracellular domain.

Fig.1 Domain organization of α-neurexins and β-neurexins. (Reissner, 2013)

The intracellular sequences of neurexins are responsible for binding to a series of presynaptic proteins, such as synaptotagmin, the postsynaptic density-95/discs large/zona-occludens-1 (PDZ) domains of peripheral plasma membrane protein CASK, and Msx2-interacting protein. The neurexin extracellular domains are responsible for binding to a variety of functional proteins, such as postsynaptic neuroligins, neurexophilin, cerebellin, leucine-rich repeat transmembrane protein, and dystroglycan.

Synaptic Functions of Neurexin

Neurexins are extensively involved in a series of synaptic bio functions, including synaptic formation, synaptic differentiation, synaptic maturation, and signal transmission among the synapses, through interacting with specific ligands. Both α-neurexins and β-neurexins can interact with neuroligins in a Ca²⁺-dependent manner. The interaction of neurexins on pre-synaptic membranes with neuroligins on post-synaptic membranes results in neuron adhesion, exerting a significant role in synapse formation and synaptic specificity. Furthermore, neurexins and neuroligins interactions also have a regulatory action on the formation of glutamatergic and GABAergic synapses, affecting neuronal excitation and inhibition. In addition to neuroligins, α-neurexins can also bind to dystroglycan in a Ca²⁺-dependent manner and are specific to neurexophilin in a Ca²⁺-independent manner. However, the functional mechanism and significance of these interactions still need to be further investigated.

Fig.2 Structure of the trans-synaptic neurexin-neuroligin complex. (Reichelt, 2012)

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References

1. Reissner, C.; et al. Neurexins. Genome Biology. 2013, 14: 213.
2. Reichelt, A.C.; et al. The role of neurexins in schizophrenia and autistic spectrum disorder. Neuropharmacology. 2012, 62: 1519-1526.