Heart failure leads to altered β2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,K ATPase microdomain.

Abstract

AIMS:

Cyclic adenosine monophosphate (cAMP) regulates cardiac excitation-contraction coupling by acting in microdomains associated with sarcolemmal ion channels. However, local real time cAMP dynamics in such microdomains has not been visualized before. We sought to directly monitor cAMP in a microdomain formed around sodium-potassium ATPase (NKA) in healthy and failing cardiomyocytes and to better understand alterations of cAMP compartmentation in heart failure.

METHODS AND RESULTS:

A novel Förster resonance energy transfer (FRET)-based biosensor termed phospholemman (PLM)-Epac1 was developed by fusing a highly sensitive cAMP sensor Epac1-camps to the C-terminus of PLM. Live cell imaging in PLM-Epac1 and Epac1-camps expressing adult rat ventricular myocytes revealed extensive regulation of NKA/PLM microdomain-associated cAMP levels by β2-adrenoceptors (β2-ARs). Local cAMP pools stimulated by these receptors were tightly controlled by phosphodiesterase (PDE) type 3. In chronic heart failure following myocardial infarction, dramatic reduction of the microdomain-specific β2-AR/cAMP signals and β2-AR dependent PLM phosphorylation was accompanied by a pronounced loss of local PDE3 and an increase in PDE2 effects.

CONCLUSIONS:

NKA/PLM complex forms a distinct cAMP microdomain which is directly regulated by β2-ARs and is under predominant control by PDE3. In heart failure, local changes in PDE repertoire result in blunted β2-AR signalling to cAMP in the vicinity of PLM.

• Authors: Zeynep Bastug-Özel, Peter T Wright, Axel E Kraft, Davor Pavlovic, Jacqueline Howie, Alexander Froese, William Fuller, Julia Gorelik, Michael J Shattock, Viacheslav O Nikolaev
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 115 Issue 3 Pg. 546-555 (03 01 2019) ISSN: 1755-3245 [Electronic] England
• PMID: 30165515 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected].

Chemical References

• Adrb2 protein, rat
• Adrenergic beta-Agonists
• Guanine Nucleotide Exchange Factors
• Membrane Proteins
• Phosphoproteins
• Receptors, Adrenergic, beta-2
• phospholemman
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Cyclic Nucleotide Phosphodiesterases, Type 2
• Cyclic Nucleotide Phosphodiesterases, Type 3
• Atp1a1 protein, rat
• Sodium-Potassium-Exchanging ATPase

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Biosensing Techniques
• Cells, Cultured
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 2 (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 3 (metabolism)
• Disease Models, Animal
• Guanine Nucleotide Exchange Factors (metabolism)
• Heart Failure (enzymology, pathology, physiopathology)
• Male
• Membrane Proteins (metabolism)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Phosphoproteins (metabolism)
• Protein Interaction Domains and Motifs
• Rats, Sprague-Dawley
• Receptors, Adrenergic, beta-2 (drug effects, metabolism)
• Sarcolemma (drug effects, enzymology, pathology)
• Second Messenger Systems (drug effects)
• Sodium-Potassium-Exchanging ATPase (metabolism)
• Time Factors