Presynaptic Targeting of α4β2 Nicotinic Acetylcholine Receptors Is Regulated by Neurexin-1β

The mechanisms involved in the targeting of neuronal nicotinic acetylcholine receptors (AChRs), critical for their functional organization at neuronal synapses, are not well understood. We have identified a novel functional association between alpha 4 beta 2 AChRs and the presynaptic cell adhesion molecule, neurexin-1 beta. In non-neuronal tsA 201 cells, recombinant neurexin-1 beta and mature alpha 4 beta 2 AChRs form complexes. alpha 4 beta 2 AChRs and neurexin-1 beta also coimmunoprecipitate from rat brain lysates. When exogenous alpha 4 beta 2 AChRs and neurexin-1 beta are coexpressed in hippocampal neurons, they are robustly targeted to hemi-synapses formed between these neurons and cocultured tsA 201 cells expressing neuroligin-1, a postsynaptic binding partner of neurexin-1 beta. The extent of synaptic targeting is significantly reduced in similar experiments using a mutant neurexin-1 beta lacking the extracellular domain. Additionally, when alpha 4 beta 2 AChRs, alpha 7 AChRs, and neurexin-1 beta are coexpressed in the same neuron, only the alpha 4 beta 2 AChR colocalizes with neurexin-1 beta at presynaptic terminals. Collectively, these data suggest that neurexin-1 beta targets alpha 4 beta 2 AChRs to presynaptic terminals, which mature by trans-synaptic interactions between neurexins and neuroligins. Interestingly, human neurexin-1 gene dysfunctions have been implicated in nicotine dependence and in autism spectrum disorders. Our results provide novel insights as to possible mechanisms by which dysfunctional neurexins, through downstream effects on alpha 4 beta 2 AChRs, may contribute to the etiology of these neurological disorders.