Details

Autor(en) / Beteiligte

• 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

Titel

Microtubule-Mediated Regulation of β 2 AR Translation and Function in Failing Hearts

Ist Teil von

• Circulation research, 2023-11, Vol.133 (11), p.944

Ort / Verlag

United States

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• β AR (beta-1 adrenergic receptor) and β 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. 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. β AR and β AR mRNAs show differential localization in cardiomyocytes, with β AR found in the perinuclear region and β AR showing diffuse distribution throughout the cell. Disruption of microtubules induces a shift of β AR transcripts toward the perinuclear region. The close proximity between β AR transcripts and translated proteins suggests that the translation process occurs in specialized, precisely defined cellular compartments. Redistribution of β AR transcripts is microtubule-dependent, as microtubule depolymerization markedly reduces the number of functional receptors on the membrane. In failing hearts, both β AR and β 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 AR function in failing hearts. Asymmetrical microtubule-dependent trafficking dictates differential β AR and β 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 AR-mediated cyclic adenosine monophosphate signaling.