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Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors

G protein–coupled receptors (GPCRs) are important modulators of synaptic functions. A fundamental but poorly addressed question in neurobiology is how targeted GPCR trafficking is achieved. Rab GTPases are the master regulators of vesicle-mediated membrane trafficking, but their functions in the syn...

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Autores principales: Wei, Zhe, Xu, Xin, Fang, Yinquan, Khater, Mostafa, Naughton, Sean X., Hu, Gang, Terry, Alvin V., Wu, Guangyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050390/
https://www.ncbi.nlm.nih.gov/pubmed/33676895
http://dx.doi.org/10.1016/j.jbc.2021.100517
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author Wei, Zhe
Xu, Xin
Fang, Yinquan
Khater, Mostafa
Naughton, Sean X.
Hu, Gang
Terry, Alvin V.
Wu, Guangyu
author_facet Wei, Zhe
Xu, Xin
Fang, Yinquan
Khater, Mostafa
Naughton, Sean X.
Hu, Gang
Terry, Alvin V.
Wu, Guangyu
author_sort Wei, Zhe
collection PubMed
description G protein–coupled receptors (GPCRs) are important modulators of synaptic functions. A fundamental but poorly addressed question in neurobiology is how targeted GPCR trafficking is achieved. Rab GTPases are the master regulators of vesicle-mediated membrane trafficking, but their functions in the synaptic presentation of newly synthesized GPCRs are virtually unknown. Here, we investigate the role of Rab43, via dominant-negative inhibition and CRISPR–Cas9–mediated KO, in the export trafficking of α(2)-adrenergic receptor (α(2)-AR) and muscarinic acetylcholine receptor (mAChR) in primary neurons and cells. We demonstrate that Rab43 differentially regulates the overall surface expression of endogenous α(2)-AR and mAChR, as well as their signaling, in primary neurons. In parallel, Rab43 exerts distinct effects on the dendritic and postsynaptic transport of specific α(2B)-AR and M3 mAChR subtypes. More interestingly, the selective actions of Rab43 toward α(2B)-AR and M3 mAChR are neuronal cell specific and dictated by direct interaction. These data reveal novel, neuron-specific functions for Rab43 in the dendritic and postsynaptic targeting and sorting of GPCRs and imply multiple forward delivery routes for different GPCRs in neurons. Overall, this study provides important insights into regulatory mechanisms of GPCR anterograde traffic to the functional destination in neurons.
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spelling pubmed-80503902021-04-16 Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors Wei, Zhe Xu, Xin Fang, Yinquan Khater, Mostafa Naughton, Sean X. Hu, Gang Terry, Alvin V. Wu, Guangyu J Biol Chem Research Article G protein–coupled receptors (GPCRs) are important modulators of synaptic functions. A fundamental but poorly addressed question in neurobiology is how targeted GPCR trafficking is achieved. Rab GTPases are the master regulators of vesicle-mediated membrane trafficking, but their functions in the synaptic presentation of newly synthesized GPCRs are virtually unknown. Here, we investigate the role of Rab43, via dominant-negative inhibition and CRISPR–Cas9–mediated KO, in the export trafficking of α(2)-adrenergic receptor (α(2)-AR) and muscarinic acetylcholine receptor (mAChR) in primary neurons and cells. We demonstrate that Rab43 differentially regulates the overall surface expression of endogenous α(2)-AR and mAChR, as well as their signaling, in primary neurons. In parallel, Rab43 exerts distinct effects on the dendritic and postsynaptic transport of specific α(2B)-AR and M3 mAChR subtypes. More interestingly, the selective actions of Rab43 toward α(2B)-AR and M3 mAChR are neuronal cell specific and dictated by direct interaction. These data reveal novel, neuron-specific functions for Rab43 in the dendritic and postsynaptic targeting and sorting of GPCRs and imply multiple forward delivery routes for different GPCRs in neurons. Overall, this study provides important insights into regulatory mechanisms of GPCR anterograde traffic to the functional destination in neurons. American Society for Biochemistry and Molecular Biology 2021-03-04 /pmc/articles/PMC8050390/ /pubmed/33676895 http://dx.doi.org/10.1016/j.jbc.2021.100517 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Wei, Zhe
Xu, Xin
Fang, Yinquan
Khater, Mostafa
Naughton, Sean X.
Hu, Gang
Terry, Alvin V.
Wu, Guangyu
Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors
title Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors
title_full Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors
title_fullStr Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors
title_full_unstemmed Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors
title_short Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein–coupled receptors
title_sort rab43 gtpase directs postsynaptic trafficking and neuron-specific sorting of g protein–coupled receptors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050390/
https://www.ncbi.nlm.nih.gov/pubmed/33676895
http://dx.doi.org/10.1016/j.jbc.2021.100517
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