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Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology

Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide...

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Autores principales: Dhara, Madhurima, Matta, Jose A., Lei, Min, Knowland, Daniel, Yu, Hong, Gu, Shenyan, Bredt, David S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271128/
https://www.ncbi.nlm.nih.gov/pubmed/32493979
http://dx.doi.org/10.1038/s41467-020-16629-3
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author Dhara, Madhurima
Matta, Jose A.
Lei, Min
Knowland, Daniel
Yu, Hong
Gu, Shenyan
Bredt, David S.
author_facet Dhara, Madhurima
Matta, Jose A.
Lei, Min
Knowland, Daniel
Yu, Hong
Gu, Shenyan
Bredt, David S.
author_sort Dhara, Madhurima
collection PubMed
description Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide screening, we find that SAT1 selectively controls nicotinic acetylcholine receptor (nAChR) biogenesis. SAT1 specifically augments assembly of nAChRs containing α7 or α4β2, but not α6 subunits. Polyamines are classically studied as regulators of ion channel gating that engage the nAChR channel pore. In contrast, we find polyamine effects on assembly involve the nAChR cytosolic loop. Neurological studies link brain polyamines with neurodegenerative conditions. Our pharmacological and transgenic animal studies find that reducing polyamines enhances cortical neuron nAChR expression and augments nicotine-mediated neuroprotection. Taken together, we describe a most unexpected role for polyamines in regulating ion channel assembly, which provides a new avenue for nAChR neuropharmacology.
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spelling pubmed-72711282020-06-15 Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology Dhara, Madhurima Matta, Jose A. Lei, Min Knowland, Daniel Yu, Hong Gu, Shenyan Bredt, David S. Nat Commun Article Small molecule polyamines are abundant in all life forms and participate in diverse aspects of cell growth and differentiation. Spermidine/spermine acetyltransferase (SAT1) is the rate-limiting enzyme in polyamine catabolism and a primary genetic risk factor for suicidality. Here, using genome-wide screening, we find that SAT1 selectively controls nicotinic acetylcholine receptor (nAChR) biogenesis. SAT1 specifically augments assembly of nAChRs containing α7 or α4β2, but not α6 subunits. Polyamines are classically studied as regulators of ion channel gating that engage the nAChR channel pore. In contrast, we find polyamine effects on assembly involve the nAChR cytosolic loop. Neurological studies link brain polyamines with neurodegenerative conditions. Our pharmacological and transgenic animal studies find that reducing polyamines enhances cortical neuron nAChR expression and augments nicotine-mediated neuroprotection. Taken together, we describe a most unexpected role for polyamines in regulating ion channel assembly, which provides a new avenue for nAChR neuropharmacology. Nature Publishing Group UK 2020-06-03 /pmc/articles/PMC7271128/ /pubmed/32493979 http://dx.doi.org/10.1038/s41467-020-16629-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dhara, Madhurima
Matta, Jose A.
Lei, Min
Knowland, Daniel
Yu, Hong
Gu, Shenyan
Bredt, David S.
Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
title Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
title_full Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
title_fullStr Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
title_full_unstemmed Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
title_short Polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
title_sort polyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271128/
https://www.ncbi.nlm.nih.gov/pubmed/32493979
http://dx.doi.org/10.1038/s41467-020-16629-3
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