Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions
- Baylor College of Medicine, United States
- Texas Children's Hospital, United States
Abstract
Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule α-neurexin. Neurexophilins are more selectively expressed in the brain than α-neurexins, however, which led us to ask whether neurexophilins modulate the function of α-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for feeding, emotion, balance, and movement. Deletion of Neurexophilin4 caused corresponding impairments, most notably in motor learning and coordination. We demonstrated that neurexophilin4 interacts with α-neurexin and GABAARs in the cerebellum. Loss of Neurexophilin4 impaired cerebellar Golgi-granule inhibitory neurotransmission and synapse number, providing a partial explanation for the motor learning and coordination deficits observed in the Neurexophilin4 null mice. Our data illustrate how selectively expressed Neurexophilin4, an α-neurexin ligand, regulates specific synapse function and modulates cerebellar motor control.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Custom-written Matlab-based programs used to operate the recording system and perform online and offline analysis of the electrophysiology data have been made available at https://github.com/haozhaozhe/PatchClamp-ShowConnection.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (5R01NS057819)
- Huda Y Zoghbi
Autism Speaks (9120)
- Li Wang
NIH Office of the Director (R01NS100893)
- Mingshan Xue
NIH Office of the Director (R01MH117089)
- Mingshan Xue
Brain and Behavior Research Foundation (NARSAD Young Investigator Award)
- Mingshan Xue
NIH Office of the Director (F31NS101891)
- Amanda M Brown
American Epilepsy Society (Predoctal fellowship)
- Wu Chen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were housed in an AAALAS-certified animal facility. All procedures to maintain and use these mice were approved by the Institutional Animal Care and Use committee for Baylor College of Medicine. Animal protocol number AN-1013.
Copyright
© 2019, Meng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions
eLife 8:e46773.
https://doi.org/10.7554/eLife.46773
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We present near-atomic-resolution cryoEM structures of the mammalian voltage-gated potassium channel Kv1.2 in open, C-type inactivated, toxin-blocked and sodium-bound states at 3.2 Å, 2.5 Å, 3.2 Å, and 2.9 Å. These structures, all obtained at nominally zero membrane potential in detergent micelles, reveal distinct ion-occupancy patterns in the selectivity filter. The first two structures are very similar to those reported in the related Shaker channel and the much-studied Kv1.2–2.1 chimeric channel. On the other hand, two new structures show unexpected patterns of ion occupancy. First, the toxin α-Dendrotoxin, like Charybdotoxin, is seen to attach to the negatively-charged channel outer mouth, and a lysine residue penetrates into the selectivity filter, with the terminal amine coordinated by carbonyls, partially disrupting the outermost ion-binding site. In the remainder of the filter two densities of bound ions are observed, rather than three as observed with other toxin-blocked Kv channels. Second, a structure of Kv1.2 in Na+ solution does not show collapse or destabilization of the selectivity filter, but instead shows an intact selectivity filter with ion density in each binding site. We also attempted to image the C-type inactivated Kv1.2 W366F channel in Na+ solution, but the protein conformation was seen to be highly variable and only a low-resolution structure could be obtained. These findings present new insights into the stability of the selectivity filter and the mechanism of toxin block of this intensively studied, voltage-gated potassium channel.
