Caveolae-associated cAMP/Ca 2+ -mediated mechano-chemical signal transduction in mouse atrial myocytes.

Autor: Medvedev RY; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA., Turner DGP; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA., DeGuire FC; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA., Leonov V; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA., Lang D; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA; Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Gorelik J; National Heart and Lung Institute, Imperial College London, London, United Kingdom., Alvarado FJ; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA., Bondarenko VE; Department of Mathematics and Statistics, Georgia State University, Atlanta, GA, USA., Glukhov AV; Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA. Electronic address: aglukhov@medicine.wisc.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2023 Nov; Vol. 184, pp. 75-87. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1016/j.yjmcc.2023.10.004
Abstrakt: Caveolae are tiny invaginations in the sarcolemma that buffer extra membrane and contribute to mechanical regulation of cellular function. While the role of caveolae in membrane mechanosensation has been studied predominantly in non-cardiomyocyte cells, caveolae contribution to cardiac mechanotransduction remains elusive. Here, we studied the role of caveolae in the regulation of Ca 2+ signaling in atrial cardiomyocytes. In Langendorff-perfused mouse hearts, atrial pressure/volume overload stretched atrial myocytes and decreased caveolae density. In isolated cells, caveolae were disrupted through hypotonic challenge that induced a temporal (<10 min) augmentation of Ca 2+ transients and caused a rise in Ca 2+ spark activity. Similar changes in Ca 2+ signaling were observed after chemical (methyl-β-cyclodextrin) and genetic ablation of caveolae in cardiac-specific conditional caveolin-3 knock-out mice. Acute disruption of caveolae, both mechanical and chemical, led to the elevation of cAMP level in the cell interior, and cAMP-mediated augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at Ser 2030 and Ser 2808 ). Caveolae-mediated stimulatory effects on Ca 2+ signaling were abolished via inhibition of cAMP production by adenyl cyclase antagonists MDL12330 and SQ22536, or reduction of PKA activity by H-89. A compartmentalized mathematical model of mouse atrial myocytes linked the observed changes to a microdomain-specific decrease in phosphodiesterase activity, which disrupted cAMP signaling and augmented PKA activity. Our findings add a new dimension to cardiac mechanobiology and highlight caveolae-associated cAMP/PKA-mediated phosphorylation of Ca 2+ handling proteins as a novel component of mechano-chemical feedback in atrial myocytes.
(Copyright © 2023. Published by Elsevier Ltd.)
Databáze: MEDLINE
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