Structure, function, and pathology of Neurexin-3

Abstract

Neurexin-3 is primarily localized in the presynaptic membrane and forms complexes with various ligands located in the postsynaptic membrane. Neurexin-3 has important roles in synapse development and synapse functions. Neurexin-3 mediates excitatory presynaptic differentiation by interacting with leucine-rich-repeat transmembrane neuronal proteins. Meanwhile, neurexin-3 modulates the expression of presynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors and γ-aminobutyric acid A receptors by interacting with neuroligins at excitatory and inhibitory synapses. Numerous studies have documented the potential contribution of neurexin-3 to neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease, addiction behaviors, and other diseases, which raises hopes that understanding the mechanisms of neurexin-3 may hold the key to developing new strategies for related illnesses. This review comprehensively covers the literature to provide current knowledge of the structure, function, and clinical role of neurexin-3.

Keywords: Excitatory synapses; Inhibitory synapses; Neural cell adhesion molecules; Neurexin-3; Neurodegenerative diseases; Neuropsychiatric diseases.

Figure 1

Amino acid sequence alignment of the LNS domains of the neurexin family. The LNS domains of neurexin-3α and neurexin-3β are followed by a sequence that consists of large numbers of threonines and serines, and the sequence may putatively represent the carbohydrate attachment sequence (CHO).

Figure 2

Structures of neurexin-3α and neurexin-3β. The extracellular sequence of neurexin-3α comprises an N-terminal signal peptide (SP) followed by three copies of a long repeat that contains a central epidermal growth factor (EGF)-like domain flanked by LNS domains (laminin, neurexin, sex-hormone-binding globulin domains), and the LNS domain of neurexin-3α is followed by a sequence that consists of large numbers of threonines and serines. This sequence may putatively represent the carbohydrate attachment sequence (CHO). Neurexin-3α is mainly anchored in the presynaptic membrane through a single transmembrane region (TMR) and ends in a short intracellular sequence that includes the PDZ II interaction site. Neurexin-3α contains four alternative splice sites (SS1, SS3, SS4, and SS5). The extracellular region of neurexin-3β contains an SP, an LNS domain and a CHO. Neurexin-3β is also anchored in the presynaptic membrane by a TMR and ends in a short tail. Neurexin-3β consists of only two alternative splice sites (SS4 and SS5).

Figure 3

Two signaling pathways reported based on synaptic junctions formed by neurexin-3 that alter synaptic function. To date, the complete signaling pathway responsible for the change in synaptic function in response to the expression of neurexin-3 has not been fully explained; however, the association of neurexin-3 with AMPARs and GABA_ARs signaling pathways has been observed. At excitatory synapses, by blocking neuroligin-1 pairing, neurexin-3β (SS4+) prevents postsynaptic density-95 (PSD-95) from recruiting specific postsynaptic proteins that are present in glutamate synapses, including AMPARs. PSD-95 binds to guanylate kinase-associated protein (GKAP), which is an adaptor protein, and GKAP binds to SHANKs. Moreover, neurexin-3β (SS4+) promotes the endocytosis of AMPARs in the postsynaptic membrane. At inhibitory synapses, neurexin-3α (SS4+) interacts with neuroligin-2 and specifically activates collybistin. Neuroligin-2 and activated collybistin are involved in the recruitment of gephyrin, which then recruits GABA_ARs to the postsynaptic membrane. In addition, neurexin-3α located in the presynaptic membrane acts directly on postsynaptic GABA_ARs.