Microtubule-mediated regulation of  β2AR translation and unction in failing hearts

Kwan, Zoe and Nadappuram, Binoy P. and Leung, Manton M. and Kondrashov, Alexander and Mohagaonkar, Sanika and Li, Ao and Amaradasa, Kumuthu S. and Chen, Ji and Rothery, Stephen and Kibreab, Iyobel and Fu, Jiarong and Sanchez-Alonso, Jose L. and Mansfield, Catherine A. and Subramanian, Hariharan and Wright, Peter T. and Swiatlowska, Pamela and Nikolaev, Viacheslav O. and Wojciak-Stothard, Beata and Ivanov, Aleksandar P. and Edel, Joshua B. and Gorelik, Julia (2023) Microtubule-mediated regulation of  β2AR translation and unction in failing hearts. Circulation Research, 133. 944–958. ISSN 0009-7330 (https://doi.org/10.1161/circresaha.123.323174)

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Abstract

Background: Beta-1 adrenergic receptor (β 1 AR)- and Beta-2 adrenergic receptor (β 2 AR)-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 t-tubule remodeling, leading to distorted β 2 AR-mediated cyclic adenosine monophosphate signaling.

ORCID iDs

Kwan, Zoe, Nadappuram, Binoy P. ORCID logoORCID: https://orcid.org/0000-0002-1386-8357, Leung, Manton M., Kondrashov, Alexander, Mohagaonkar, Sanika, Li, Ao, Amaradasa, Kumuthu S., Chen, Ji, Rothery, Stephen, Kibreab, Iyobel, Fu, Jiarong, Sanchez-Alonso, Jose L., Mansfield, Catherine A., Subramanian, Hariharan, Wright, Peter T., Swiatlowska, Pamela, Nikolaev, Viacheslav O., Wojciak-Stothard, Beata, Ivanov, Aleksandar P., Edel, Joshua B. and Gorelik, Julia;
  • Item type:Article
    ID code:88732
    Dates:
    Date
    Event
    23 October 2023
    Published
    23 October 2023
    Published Online
    11 October 2023
    Accepted
    2 June 2023
    Submitted
    Subjects:Medicine > Internal medicine
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:16 Apr 2024 12:31
    Last modified:11 Nov 2024 14:16
    URI:https://strathprints.strath.ac.uk/id/eprint/88732
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