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LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function

Lysosomes function not only as degradatory compartments but also as dynamic intracellular calcium ion stores. The transient receptor potential mucolipin 1 (TRPML1) channel mediates lysosomal Ca(2+) release, thereby participating in multiple cellular functions. The pentameric Ragulator complex, which...

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Autores principales: Sun, Jiandong, Liu, Yan, Hao, Xiaoning, Lin, Weiju, Su, Wenyue, Chiang, Emerald, Baudry, Michel, Bi, Xiaoning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886530/
https://www.ncbi.nlm.nih.gov/pubmed/35099830
http://dx.doi.org/10.15252/embj.2021108119
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author Sun, Jiandong
Liu, Yan
Hao, Xiaoning
Lin, Weiju
Su, Wenyue
Chiang, Emerald
Baudry, Michel
Bi, Xiaoning
author_facet Sun, Jiandong
Liu, Yan
Hao, Xiaoning
Lin, Weiju
Su, Wenyue
Chiang, Emerald
Baudry, Michel
Bi, Xiaoning
author_sort Sun, Jiandong
collection PubMed
description Lysosomes function not only as degradatory compartments but also as dynamic intracellular calcium ion stores. The transient receptor potential mucolipin 1 (TRPML1) channel mediates lysosomal Ca(2+) release, thereby participating in multiple cellular functions. The pentameric Ragulator complex, which plays a critical role in the activation of mTORC1, is also involved in lysosomal trafficking and is anchored to lysosomes through its LAMTOR1 subunit. Here, we report that the Ragulator restricts lysosomal trafficking in dendrites of hippocampal neurons via LAMTOR1‐mediated tonic inhibition of TRPML1 activity, independently of mTORC1. LAMTOR1 directly interacts with TRPML1 through its N‐terminal domain. Eliminating this inhibition in hippocampal neurons by LAMTOR1 deletion or by disrupting LAMTOR1‐TRPML1 binding increases TRPML1‐mediated Ca(2+) release and facilitates dendritic lysosomal trafficking powered by dynein. LAMTOR1 deletion in the hippocampal CA1 region of adult mice results in alterations in synaptic plasticity, and in impaired object‐recognition memory and contextual fear conditioning, due to TRPML1 activation. Mechanistically, changes in synaptic plasticity are associated with increased GluA1 dephosphorylation by calcineurin and lysosomal degradation. Thus, LAMTOR1‐mediated inhibition of TRPML1 is critical for regulating dendritic lysosomal motility, synaptic plasticity, and learning.
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spelling pubmed-88865302022-03-04 LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function Sun, Jiandong Liu, Yan Hao, Xiaoning Lin, Weiju Su, Wenyue Chiang, Emerald Baudry, Michel Bi, Xiaoning EMBO J Articles Lysosomes function not only as degradatory compartments but also as dynamic intracellular calcium ion stores. The transient receptor potential mucolipin 1 (TRPML1) channel mediates lysosomal Ca(2+) release, thereby participating in multiple cellular functions. The pentameric Ragulator complex, which plays a critical role in the activation of mTORC1, is also involved in lysosomal trafficking and is anchored to lysosomes through its LAMTOR1 subunit. Here, we report that the Ragulator restricts lysosomal trafficking in dendrites of hippocampal neurons via LAMTOR1‐mediated tonic inhibition of TRPML1 activity, independently of mTORC1. LAMTOR1 directly interacts with TRPML1 through its N‐terminal domain. Eliminating this inhibition in hippocampal neurons by LAMTOR1 deletion or by disrupting LAMTOR1‐TRPML1 binding increases TRPML1‐mediated Ca(2+) release and facilitates dendritic lysosomal trafficking powered by dynein. LAMTOR1 deletion in the hippocampal CA1 region of adult mice results in alterations in synaptic plasticity, and in impaired object‐recognition memory and contextual fear conditioning, due to TRPML1 activation. Mechanistically, changes in synaptic plasticity are associated with increased GluA1 dephosphorylation by calcineurin and lysosomal degradation. Thus, LAMTOR1‐mediated inhibition of TRPML1 is critical for regulating dendritic lysosomal motility, synaptic plasticity, and learning. John Wiley and Sons Inc. 2022-01-31 2022-03-01 /pmc/articles/PMC8886530/ /pubmed/35099830 http://dx.doi.org/10.15252/embj.2021108119 Text en © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Articles
Sun, Jiandong
Liu, Yan
Hao, Xiaoning
Lin, Weiju
Su, Wenyue
Chiang, Emerald
Baudry, Michel
Bi, Xiaoning
LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function
title LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function
title_full LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function
title_fullStr LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function
title_full_unstemmed LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function
title_short LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function
title_sort lamtor1 inhibition of trpml1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886530/
https://www.ncbi.nlm.nih.gov/pubmed/35099830
http://dx.doi.org/10.15252/embj.2021108119
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