Dystroglycan Binding to α-Neurexin Competes with Neurexophilin-1 and Neuroligin in the Brain

Reißner, Carsten; Stahn, J.; Breuer, Dorothee; Klose, Martin; Pohlentz, Gottfried; Mormann, Michael; Missler, Markus

doi:10.1074/jbc.m114.595413

Cited by 67 publications

(82 citation statements)

References 121 publications

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“…Human NRXN3 constructs (SS4−) were based on previously described plasmids (25). Plasmids encoding separate LNS domains of Nrxn1α with C-terminal Fc tags have been previously described (36). PCR products from various neurexin cDNA clones and isothermal assembly into the pEGFP vector (Clontech) were used to generate plasmids encoding full-length Nrxn1 and Nrxn3 isoforms with C-terminal (intracellular) GFP fusion.…”

Section: Methodsmentioning

confidence: 99%

Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

Sterky

Trotter

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

117

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Establishment, specification, and validation of synaptic connections are thought to be mediated by interactions between pre- and postsynaptic cell-adhesion molecules. Arguably, the best-characterized transsynaptic interactions are formed by presynaptic neurexins, which bind to diverse postsynaptic ligands. In a proteomic screen of neurexin-1 (Nrxn1) complexes immunoisolated from mouse brain, we identified carbonic anhydrase-related proteins CA10 and CA11, two homologous, secreted glycoproteins of unknown function that are predominantly expressed in brain. We found that CA10 directly binds in a cis configuration to a conserved membrane-proximal, extracellular sequence of α- and β-neurexins. The CA10–neurexin complex is stable and stoichiometric, and results in formation of intermolecular disulfide bonds between conserved cysteine residues in neurexins and CA10. CA10 promotes surface expression of α- and β-neurexins, suggesting that CA10 may form a complex with neurexins in the secretory pathway that facilitates surface transport of neurexins. Moreover, we observed that the Nrxn1 gene expresses from an internal 3′ promoter a third isoform, Nrxn1γ, that lacks all Nrxn1 extracellular domains except for the membrane-proximal sequences and that also tightly binds to CA10. Our data expand the understanding of neurexin-based transsynaptic interaction networks by providing further insight into the interactions nucleated by neurexins at the synapse.

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Section: Methodsmentioning

confidence: 99%

Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

Sterky

Trotter

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

117

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“…A unifying trend for the binding function of NRXN is the importance of SS4. Indeed, NRXN interaction with their numerous ligands depends on the splicing events at SS4 (87,88,(90)(91)(92). Like for other NRXN ligands, alternative splicing at SS4 regulates the binding to LPHN1.…”

Section: Neurexinsmentioning

confidence: 98%

Latrophilins updated

Meza-Aguilar

Boucard

2014

Biomolecular Concepts

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Latrophilins (LPHN) are part of a yet unexplored family of receptors comprising three isoforms, LPHN1-3, and belonging to a unique branch of G protein-coupled receptors (GPCR) named adhesion GPCR (aGPCR). LPHN are considered to be prototypical models for the study of aGPCR as they are one of the most evolutionary conserved members. Previously described as the target for a potent neurotoxin from the black widow spider venom, LPHN are now being studied under a whole new perspective. Indeed, recent advances have provided a better understanding of different aspects of this prototypical family of receptors: 1) elucidation of LPHN ectodomain organization by crystallography has unveiled a new functional domain with great repercussion on all the other members of the aGPCR family, 2) proteomic approaches have opened the gate to unsuspected functional characteristics of LPHN cellular role, and 3) genetic approaches have provided hints into the physiological functions of LPHN in specific systems and organisms. Moreover, genomic linkage studies screening human patients from diverse genetic backgrounds have involved LPHN gene defects in human disorders such as attention-deficit hyperactivity disorder and cancer. In this review, we will provide a historical perspective addressing experimental research on these receptors while highlighting the new advances and discoveries concerning LPHN functions. As GPCR still represent the most studied targets for the development of pharmacological approaches aiming at alleviating human disorders, the relevance of studying LPHN retains a high pertinence to better understand these receptors for the treatment of human diseases.

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“…Another a-neurexin-specific ligand, neurexophilin-1, which shows limited expression in subpopulations of inhibitory neurons, instructs short-term synaptic plasticity at inhibitory synapses, and maintains presynaptic GABA B and postsynaptic GABA A receptors [76]. Moreover, neurexophilin-1 competes with dystroglycans for binding to a-neurexins [77]. Thus, various classes of inhibitory synaptic molecules are involved in different forms of synaptic plasticity, cooperatively driving the activity-dependent rewiring of local microcircuits and maintaining the E/ I balance in the brain.…”

Section: Regulation Of Inhibitory Synaptic Plasticitymentioning

confidence: 99%

The balancing act of GABAergic synapse organizers

Choii

2015

Trends in Molecular Medicine

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Dystroglycan Binding to α-Neurexin Competes with Neurexophilin-1 and Neuroligin in the Brain

Cited by 67 publications

References 121 publications

Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

Latrophilins updated

The balancing act of GABAergic synapse organizers

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