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Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts
BACKGROUND: β(1)AR (beta-1 adrenergic receptor) and β(2)AR (beta-2 adrenergic receptor)-mediated cyclic adenosine monophosphate signaling has distinct effects on cardiac function and heart failure progression. However, the mechanism regulating spatial localization and functional compartmentation of...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635332/ https://www.ncbi.nlm.nih.gov/pubmed/37869877 http://dx.doi.org/10.1161/CIRCRESAHA.123.323174 |
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author | Kwan, Zoe Paulose Nadappuram, Binoy Leung, Manton M. Mohagaonkar, Sanika Li, Ao Amaradasa, Kumuthu S. Chen, Ji Rothery, Stephen Kibreab, Iyobel Fu, Jiarong Sanchez-Alonso, Jose L. Mansfield, Catherine A. Subramanian, Hariharan Kondrashov, Alexander Wright, Peter T. Swiatlowska, Pamela Nikolaev, Viacheslav O. Wojciak-Stothard, Beata Ivanov, Aleksandar P. Edel, Joshua B. Gorelik, Julia |
author_facet | Kwan, Zoe Paulose Nadappuram, Binoy Leung, Manton M. Mohagaonkar, Sanika Li, Ao Amaradasa, Kumuthu S. Chen, Ji Rothery, Stephen Kibreab, Iyobel Fu, Jiarong Sanchez-Alonso, Jose L. Mansfield, Catherine A. Subramanian, Hariharan Kondrashov, Alexander Wright, Peter T. Swiatlowska, Pamela Nikolaev, Viacheslav O. Wojciak-Stothard, Beata Ivanov, Aleksandar P. Edel, Joshua B. Gorelik, Julia |
author_sort | Kwan, Zoe |
collection | PubMed |
description | BACKGROUND: β(1)AR (beta-1 adrenergic receptor) and β(2)AR (beta-2 adrenergic receptor)-mediated cyclic adenosine monophosphate signaling has distinct effects on cardiac function and heart failure progression. However, the mechanism regulating spatial localization and functional compartmentation of cardiac β-ARs remains elusive. Emerging evidence suggests that microtubule-dependent trafficking of mRNP (messenger ribonucleoprotein) and localized protein translation modulates protein compartmentation in cardiomyocytes. We hypothesized that β-AR compartmentation in cardiomyocytes is accomplished by selective trafficking of its mRNAs and localized translation. METHODS: The localization pattern of β-AR mRNA was investigated using single molecule fluorescence in situ hybridization and subcellular nanobiopsy in rat cardiomyocytes. The role of microtubule on β-AR mRNA localization was studied using vinblastine, and its effect on receptor localization and function was evaluated with immunofluorescent and high-throughput Förster resonance energy transfer microscopy. An mRNA protein co-detection assay identified plausible β-AR translation sites in cardiomyocytes. The mechanism by which β-AR mRNA is redistributed post–heart failure was elucidated by single molecule fluorescence in situ hybridization, nanobiopsy, and high-throughput Förster resonance energy transfer microscopy on 16 weeks post–myocardial infarction and detubulated cardiomyocytes. RESULTS: β(1)AR and β(2)AR mRNAs show differential localization in cardiomyocytes, with β(1)AR found in the perinuclear region and β(2)AR showing diffuse distribution throughout the cell. Disruption of microtubules induces a shift of β(2)AR transcripts toward the perinuclear region. The close proximity between β(2)AR transcripts and translated proteins suggests that the translation process occurs in specialized, precisely defined cellular compartments. Redistribution of β(2)AR transcripts is microtubule-dependent, as microtubule depolymerization markedly reduces the number of functional receptors on the membrane. In failing hearts, both β(1)AR and β(2)AR mRNAs are redistributed toward the cell periphery, similar to what is seen in cardiomyocytes undergoing drug-induced detubulation. This suggests that t-tubule remodeling contributes to β-AR mRNA redistribution and impaired β(2)AR function in failing hearts. CONCLUSIONS: Asymmetrical microtubule-dependent trafficking dictates differential β(1)AR and β(2)AR localization in healthy cardiomyocyte microtubules, underlying the distinctive compartmentation of the 2 β-ARs on the plasma membrane. The localization pattern is altered post–myocardial infarction, resulting from transverse tubule remodeling, leading to distorted β(2)AR-mediated cyclic adenosine monophosphate signaling. |
format | Online Article Text |
id | pubmed-10635332 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-106353322023-11-15 Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts Kwan, Zoe Paulose Nadappuram, Binoy Leung, Manton M. Mohagaonkar, Sanika Li, Ao Amaradasa, Kumuthu S. Chen, Ji Rothery, Stephen Kibreab, Iyobel Fu, Jiarong Sanchez-Alonso, Jose L. Mansfield, Catherine A. Subramanian, Hariharan Kondrashov, Alexander Wright, Peter T. Swiatlowska, Pamela Nikolaev, Viacheslav O. Wojciak-Stothard, Beata Ivanov, Aleksandar P. Edel, Joshua B. Gorelik, Julia Circ Res Original Research BACKGROUND: β(1)AR (beta-1 adrenergic receptor) and β(2)AR (beta-2 adrenergic receptor)-mediated cyclic adenosine monophosphate signaling has distinct effects on cardiac function and heart failure progression. However, the mechanism regulating spatial localization and functional compartmentation of cardiac β-ARs remains elusive. Emerging evidence suggests that microtubule-dependent trafficking of mRNP (messenger ribonucleoprotein) and localized protein translation modulates protein compartmentation in cardiomyocytes. We hypothesized that β-AR compartmentation in cardiomyocytes is accomplished by selective trafficking of its mRNAs and localized translation. METHODS: The localization pattern of β-AR mRNA was investigated using single molecule fluorescence in situ hybridization and subcellular nanobiopsy in rat cardiomyocytes. The role of microtubule on β-AR mRNA localization was studied using vinblastine, and its effect on receptor localization and function was evaluated with immunofluorescent and high-throughput Förster resonance energy transfer microscopy. An mRNA protein co-detection assay identified plausible β-AR translation sites in cardiomyocytes. The mechanism by which β-AR mRNA is redistributed post–heart failure was elucidated by single molecule fluorescence in situ hybridization, nanobiopsy, and high-throughput Förster resonance energy transfer microscopy on 16 weeks post–myocardial infarction and detubulated cardiomyocytes. RESULTS: β(1)AR and β(2)AR mRNAs show differential localization in cardiomyocytes, with β(1)AR found in the perinuclear region and β(2)AR showing diffuse distribution throughout the cell. Disruption of microtubules induces a shift of β(2)AR transcripts toward the perinuclear region. The close proximity between β(2)AR transcripts and translated proteins suggests that the translation process occurs in specialized, precisely defined cellular compartments. Redistribution of β(2)AR transcripts is microtubule-dependent, as microtubule depolymerization markedly reduces the number of functional receptors on the membrane. In failing hearts, both β(1)AR and β(2)AR mRNAs are redistributed toward the cell periphery, similar to what is seen in cardiomyocytes undergoing drug-induced detubulation. This suggests that t-tubule remodeling contributes to β-AR mRNA redistribution and impaired β(2)AR function in failing hearts. CONCLUSIONS: Asymmetrical microtubule-dependent trafficking dictates differential β(1)AR and β(2)AR localization in healthy cardiomyocyte microtubules, underlying the distinctive compartmentation of the 2 β-ARs on the plasma membrane. The localization pattern is altered post–myocardial infarction, resulting from transverse tubule remodeling, leading to distorted β(2)AR-mediated cyclic adenosine monophosphate signaling. Lippincott Williams & Wilkins 2023-10-23 2023-11-10 /pmc/articles/PMC10635332/ /pubmed/37869877 http://dx.doi.org/10.1161/CIRCRESAHA.123.323174 Text en © 2023 The Authors. https://creativecommons.org/licenses/by/4.0/Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. |
spellingShingle | Original Research Kwan, Zoe Paulose Nadappuram, Binoy Leung, Manton M. Mohagaonkar, Sanika Li, Ao Amaradasa, Kumuthu S. Chen, Ji Rothery, Stephen Kibreab, Iyobel Fu, Jiarong Sanchez-Alonso, Jose L. Mansfield, Catherine A. Subramanian, Hariharan Kondrashov, Alexander Wright, Peter T. Swiatlowska, Pamela Nikolaev, Viacheslav O. Wojciak-Stothard, Beata Ivanov, Aleksandar P. Edel, Joshua B. Gorelik, Julia Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts |
title | Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts |
title_full | Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts |
title_fullStr | Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts |
title_full_unstemmed | Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts |
title_short | Microtubule-Mediated Regulation of β(2)AR Translation and Function in Failing Hearts |
title_sort | microtubule-mediated regulation of β(2)ar translation and function in failing hearts |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635332/ https://www.ncbi.nlm.nih.gov/pubmed/37869877 http://dx.doi.org/10.1161/CIRCRESAHA.123.323174 |
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