Neurexin

Neurexins (NRXNs): Molecular Role in Synapse Formation and Function

1. Structure and Isoforms

• The NRXN gene family includes NRXN1, NRXN2, and NRXN3, each producing:

  • α-neurexins (long isoforms, ~1,500 amino acids): extracellular domains with multiple laminin–neurexin–sex-hormone-binding globulin (LNS) domains and EGF-like repeats.

  • β-neurexins (short isoforms): contain only the terminal LNS domain.

• Alternative splicing at several canonical sites (>1000 variants) allows synapse-type-specific molecular codes — this defines what kinds of partners (neuroligins, LRRTMs, cerebellins, etc.) each NRXN can bind.

2. Presynaptic Localization and Anchoring

• NRXNs are integral membrane proteins located in the presynaptic active zone.

• Their C-terminal intracellular PDZ-binding motif interacts with scaffolding proteins such as:

  • CASK, Mint1, and Veli, forming a complex that anchors NRXNs to voltage-gated Ca²⁺ channels (VGCCs) and synaptic vesicle release sites.

• This coupling ensures precise alignment between Ca²⁺ influx and synaptic vesicle fusion.

3. Trans-Synaptic Adhesion

• Extracellularly, NRXNs bind to postsynaptic neuroligins (NLGNs) or LRRTMs across the synaptic cleft.

• The NRXN–NLGN complex forms a trans-synaptic molecular bridge:

  • NRXN (presynaptic) → links to vesicle release machinery

  • NLGN (postsynaptic) → binds PSD-95, SHANK, Homer, and actin cytoskeleton

• This coupling ensures synapse specification, meaning glutamatergic vs. GABAergic identity and functional tuning.

4. Regulation of Synaptic Vesicle Release

• NRXNs modulate presynaptic Ca²⁺ channel clustering:

  • Particularly P/Q-type (CaV2.1) and N-type (CaV2.2) channels.

  • They recruit RIM and Munc13, key components of the active zone vesicle priming complex.

• The result: faster, more synchronized neurotransmitter release in response to action potentials.

5. Signaling and Plasticity

• NRXNs are dynamic — their extracellular domains can be glycosylated or modified by heparan sulfate, influencing partner affinity.

• Activity-dependent signaling (e.g., via Ca²⁺ influx) can alter NRXN splicing or post-translational modification.

• This regulates short-term plasticity, homeostatic scaling, and synapse maintenance.

6. Pathophysiological Relevance

• Mutations or deletions in NRXN1 are linked to:

  • Autism spectrum disorder (ASD)

  • Schizophrenia

  • Epilepsy

• These conditions involve synaptic miswiring, altered vesicle release probability, and defective excitatory/inhibitory balance.

7. Molecular Network Summary

Function	Molecular Partners	Consequence
Adhesion	Neuroligins, LRRTMs	Defines synapse type
Anchoring	CASK, Mint1, Veli	Aligns active zone with postsynaptic density
Release control	RIM, Munc13, Ca²⁺ channels	Regulates vesicle fusion timing
Plasticity	Heparan sulfate, alternative splicing	Dynamic tuning of synaptic strength