Loss of caveolar A1 adenosine receptor signalling blunts anti-adrenergic control in heart failure

Clicks: 1
ID: 318651
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal

Ranked #99 of 103 articles by views in cardiovascular research

Most read Least read

Bar heights use a square-root scale.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
AIMS: Adenosine, acting through A1 adenosine receptors (A1ARs), exerts anti-adrenergic effects by inhibiting β1-adrenergic receptor (β1AR)-mediated cAMP production and contractility in the heart. While the functional interaction between A1ARs and β1ARs is well established in both atrial and ventricular myocytes, the subcellular compartmentalisation of this crosstalk and how it is disrupted in heart failure (HF) remains incompletely understood. This study investigates the spatial confinement of A1AR-β1AR signalling within atrial microdomains and assesses how structural remodelling in HF alters this regulatory axis. METHODS AND RESULTS: qPCR analysis revealed that A1AR is the predominant adenosine receptor subtype in both rat and human atrial tissues. In healthy rat and mouse atrial myocytes, A1AR activation reduced β1AR-induced cAMP production and sarcomere shortening, with suppression of cAMP signals at sarcolemmal microdomains enriched in PKA type II. This was further supported by Scanning Ion Conductance Microscopy (SICM)-guided scanning patch-clamp showed that A1AR suppressed β1AR-driven L-type Ca2+ channel (LTCC) activity at both T-tubule and crest membrane domains. In atrial myocytes isolated from failing rat and human hearts, A1AR-mediated inhibition of β1AR-induced cAMP production and contractility was impaired. Caveolar disruption by methyl-β-cyclodextrin in rat atrial myocytes or via cardiac-specific caveolin-3 knockout in mice abolished this A1AR-mediated inhibition. Notably, cholesterol repletion alone did not restore membrane cAMP regulation, whereas Cav3 over-expression rescued A1AR-dependent suppression, supporting a requirement for Cav3-dependent organisation. In mouse atrial preparations isolated from failing hearts, high-resolution optical mapping showed that A1AR-mediated anti-adrenergic regulation of Ca2+ cycling was selectively lost in the intercaval region, correlating with the regional absence of T-tubule and downregulation of caveolae structures. CONCLUSIONS: A1ARs provide anti-adrenergic restraint of β1AR signalling through Cav3-dependent membrane organisation. In HF, regional caveolar disorganisation uncouples this protective pathway, contributing to spatially heterogeneous Ca2+ dysregulation in the atrium. TRANSLATIONAL PERSPECTIVE: Adenosine acting via A1 receptors provides an endogenous constraint on β-adrenergic signalling in the atria. We show that this protection relies on Cav3-dependent caveolar organisation and is lost in heart failure, particularly in the inter-caval region of the right atrium where caveolae density is downregulated. Diminished A1 anti-adrenergic control permits enhanced β1AR-cAMP-Ca2+ signalling and regional Ca2+ dysregulation, a substrate linked to atrial ectopy and atrial fibrillation in structural heart disease. These findings identify membrane microdomain integrity as a determinant of atrial autonomic balance and suggest that stabilising caveolar organisation may help restore adenosine-mediated restraint in heart failure.
Reference Key
openalex_W7165783498 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Marta Mazzola, H Wang, Di Lang, Marina Balycheva, Navneet Bhogal, Jose L. Sanchez‐Alonso, Ivan Diakonov, Carla Lucarelli, En-Chi Lai, Prakash P Punjabi, Michele Miragoli, Giuseppe Faggian, Alexey V. Glukhov, Julia Gorelik
Journal cardiovascular research
Year 2026
DOI
10.1093/cvr/cvag131
URL
https://doi.org/10.1093/cvr/cvag131
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.