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Control of Synaptic Levels of Nicotinic Acetylcholine Receptor by the Sequestering Subunit Dα5 and Secreted Scaffold Protein Hig

Authors :
Minoru Nakayama
Osamu Nishimura
Yuhi Nishimura
Miwa Kitaichi
Shigehiro Kuraku
Masaki Sone
Chihiro Hama
Source :
The Journal of Neuroscience. 43:3989-4004
Publication Year :
2023
Publisher :
Society for Neuroscience, 2023.

Abstract

The presentation of nicotinic acetylcholine receptors (nAChRs) on synaptic membranes is crucial for generating cholinergic circuits, some of which are associated with memory function and neurodegenerative disorders. Although the physiology and structure of nAChR, a cation channel comprising five subunits, have been extensively studied, little is known about how the receptor levels in interneuronal synapses are determined and which nAChR subunits participate in the regulatory process in cooperation with synaptic cleft matrices and intracellular proteins. By a genetic screen ofDrosophila, we identified mutations in the nAChR subunit Dα5 gene as suppressors that restored the mutant phenotypes ofhig, which encodes a secretory matrix protein localized to cholinergic synaptic clefts in the brain. Only the loss of function of Dα5 among the 10 nAChR subunits suppressedhigmutant phenotypes in both male and female flies. Dα5 behaved as a lethal factor when Hig was defective; loss of Dα5 inhigmutants rescued lethality, upregulating Dα6 synaptic levels. By contrast, levels of Dα5, Dα6, and Dα7 subunits were all reduced inhigmutants. These three subunits have distinct properties for interaction with Hig or trafficking, as confirmed by chimeric subunit experiments. Notably, the chimeric Dα5 protein, which has the extracellular sequences that display no positive interaction with Hig, exhibited abnormal distribution and lethality even in the presence of Hig. We propose that the sequestering subunit Dα5 functions by reducing synaptic levels of nAChR through internalization, and this process is blocked by Hig, which tethers Dα5 to the synaptic cleft matrix.SIGNIFICANCE STATEMENTBecause the cholinergic synapse is one of the major synapses that generate various brain functions, numerous studies have sought to reveal the physiology and structure of the nicotinic acetylcholine receptor (nAChR). However, little is known about how synaptic levels of nAChR are controlled and which nAChR subunits participate in the regulatory process in cooperation with synaptic cleft matrices. By a genetic screen ofDrosophila, we identified mutations in the nAChR subunit Dα5 gene as suppressors that restored the mutant phenotypes ofhig, which encodes a secretory matrix protein localized to cholinergic synaptic clefts. Our data indicate that Dα5 functions in reducing synaptic levels of nAChR, and this process is blocked by Hig, which tethers Dα5 to the synaptic cleft matrix.

Subjects

Subjects :
General Neuroscience

Details

ISSN :
15292401 and 02706474
Volume :
43
Database :
OpenAIRE
Journal :
The Journal of Neuroscience
Accession number :
edsair.doi...........ec609840bec408106934ef86c32ab263
Full Text :
https://doi.org/10.1523/jneurosci.2243-21.2023