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Differential Downregulation of β 1 -Adrenergic Receptor Signaling in the Heart.
- Source :
-
Journal of the American Heart Association [J Am Heart Assoc] 2024 Jun 18; Vol. 13 (12), pp. e033733. Date of Electronic Publication: 2024 Jun 11. - Publication Year :
- 2024
-
Abstract
- Background: Chronic sympathetic stimulation drives desensitization and downregulation of β1 adrenergic receptor (β <subscript>1</subscript> AR) in heart failure. We aim to explore the differential downregulation subcellular pools of β <subscript>1</subscript> AR signaling in the heart.<br />Methods and Results: We applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice. We applied confocal and proximity ligation assay to examine β <subscript>1</subscript> AR association with L-type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and Förster resonance energy transfer-based biosensors to probe subcellular β <subscript>1</subscript> AR-PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced β <subscript>1</subscript> AR protein levels, receptor association with L-type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta/cell, 29.65 saline versus 14.17 isoproterenol, P <0.05), and receptor-induced PKA signaling at the plasma membrane (Förster resonance energy transfer, 28.9% saline versus 1.9% isoproterenol, P <0.05) and ryanodine receptor 2 complex (Förster resonance energy transfer, 30.2% saline versus 10.6% isoproterenol, P <0.05). However, the β <subscript>1</subscript> AR association with SERCA2a was enhanced (puncta/cell, 51.4 saline versus 87.5 isoproterenol, P <0.05), and the receptor signal was minimally affected. The isoproterenol-infused hearts displayed decreased PDE4D (phosphodiesterase 4D) and PDE3A and increased PDE2A, PDE4A, and PDE4B protein levels. We observed a reduced role of PDE4 and enhanced roles of PDE2 and PDE3 on the β <subscript>1</subscript> AR-PKA activity at the ryanodine receptor 2 complexes and myocyte shortening. Despite the enhanced β <subscript>1</subscript> AR association with SERCA2a, the endogenous norepinephrine-induced signaling was reduced at the SERCA2a complexes. Inhibiting monoamine oxidase A rescued the norepinephrine-induced PKA signaling at the SERCA2a and myocyte shortening.<br />Conclusions: This study reveals distinct mechanisms for the downregulation of subcellular β <subscript>1</subscript> AR signaling in the heart under chronic adrenergic stimulation.
- Subjects :
- Animals
Male
Disease Models, Animal
Mice
Heart Failure metabolism
Heart Failure chemically induced
Heart Failure physiopathology
Cardiomyopathies metabolism
Cardiomyopathies chemically induced
Fluorescence Resonance Energy Transfer
Receptors, Adrenergic, beta-1 metabolism
Down-Regulation
Signal Transduction
Ryanodine Receptor Calcium Release Channel metabolism
Mice, Inbred C57BL
Isoproterenol pharmacology
Cyclic AMP-Dependent Protein Kinases metabolism
Myocytes, Cardiac metabolism
Myocytes, Cardiac drug effects
Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
Calcium Channels, L-Type metabolism
Calcium Channels, L-Type drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2047-9980
- Volume :
- 13
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of the American Heart Association
- Publication Type :
- Academic Journal
- Accession number :
- 38860414
- Full Text :
- https://doi.org/10.1161/JAHA.123.033733