Microtubule-mediated regulation of β2AR translation and function in failing hearts
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
BACKGROUND: β1AR (beta-1 adrenergic receptor) and β2AR (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: β1AR and β2AR mRNAs show differential localization in cardiomyocytes, with β1AR found in the perinuclear region and β2AR showing diffuse distribution throughout the cell. Disruption of microtubules induces a shift of β2AR transcripts toward the perinuclear region. The close proximity between β2AR transcripts and translated proteins suggests that the translation process occurs in specialized, precisely defined cellular compartments. Redistribution of β2AR transcripts is microtubule-dependent, as microtubule depolymerization markedly reduces the number of functional receptors on the membrane. In failing hearts, both β1AR and β2AR 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 β2AR function in failing hearts. CONCLUSIONS: Asymmetrical microtubule-dependent trafficking dictates differential β1AR and β2AR 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 β2AR-mediated cyclic adenosine monophosphate signaling.
Date Issued
2023-11-10
Date Acceptance
2023-10-11
Citation
Circulation Research, 2023, 133 (11), pp.944-958
ISSN
0009-7330
Publisher
American Heart Association
Start Page
944
End Page
958
Journal / Book Title
Circulation Research
Volume
133
Issue
11
Copyright Statement
© 2023 The Authors. 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 License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/37869877
Subjects
Adenosine Monophosphate
Animals
Cyclic AMP
Heart Failure
In Situ Hybridization, Fluorescence
Microtubules
Myocardial Infarction
Myocytes, Cardiac
Rats
Receptors, Adrenergic, beta-1
Receptors, Adrenergic, beta-2
RNA, Messenger
animal
cardiomyocytes
heart failure
infarction
microtubules
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2023-10-23