Release-dependent feedback inhibition by a presynaptically localized ligand-gated anion channel
Abstract
Presynaptic ligand-gated ion channels (LGICs) have long been proposed to affect neurotransmitter release and to tune neural circuit activity. However, the understanding of their in vivo physiological action remains limited, partly due to the complexity in channel types and scarcity of genetic models. Here we report that C. elegans LGC-46, a member of the Cys-loop acetylcholine (ACh)-gated chloride (ACC) channel family, localizes to presynaptic terminals of cholinergic motor neurons and regulates synaptic vesicle (SV) release kinetics upon evoked release of acetylcholine. Loss of lgc-46 prolongs evoked release, without altering spontaneous activity. Conversely, a gain-of-function mutation of lgc-46 shortens evoked release to reduce synaptic transmission. This inhibition of presynaptic release requires the anion selectivity of LGC-46, and can ameliorate cholinergic over-excitation in a C. elegans model of excitation-inhibition imbalance. These data demonstrate a novel mechanism of presynaptic negative feedback in which an anion-selective LGIC acts as an auto-receptor to inhibit SV release.
Article and author information
Author details
Funding
National Institutes of Health (R01, 035546)
- Yishi Jin
Howard Hughes Medical Institute (Yishi Jin)
- Yishi Jin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Takayanagi-Kiya 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.
Metrics
-
- 1,229
- views
-
- 315
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Sleep loss increases AMPA-synaptic strength and number in the neocortex. However, this is only part of the synaptic sleep loss response. We report an increased AMPA/NMDA EPSC ratio in frontal-cortical pyramidal neurons of layers 2–3. Silent synapses are absent, decreasing the plastic potential to convert silent NMDA to active AMPA synapses. These sleep loss changes are recovered by sleep. Sleep genes are enriched for synaptic shaping cellular components controlling glutamate synapse phenotype, overlap with autism risk genes, and are primarily observed in excitatory pyramidal neurons projecting intra-telencephalically. These genes are enriched with genes controlled by the transcription factor, MEF2c, and its repressor, HDAC4. Sleep genes can thus provide a framework within which motor learning and training occur mediated by the sleep-dependent oscillation of glutamate-synaptic phenotypes.
-
- Neuroscience
- Structural Biology and Molecular Biophysics
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.