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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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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. |
format | Online Article Text |
id | pubmed-7271128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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