Impact of paroxetine on proximal beta-adrenergic receptor signaling.

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Guo S, Carter RL, Grisanti LA, Koch WJ, Tilley DG

Impact of paroxetine on proximal beta-adrenergic receptor signaling.

Cell Signal. 2017 Oct;38:127-133. doi: 10.1016/j.cellsig.2017.07.006. Epub 2017 Jul 12.

PubMed ID

28711716 [ View in PubMed

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Abstract

beta-adrenergic receptors (betaAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of betaAR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances betaAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial betaAR expression in mouse models of heart failure. Despite these functional outcomes, consistent with diminished betaAR desensitization, the proximal betaAR signaling mechanisms sensitive to paroxetine have not been reported. In this study, we aimed to determine whether paroxetine prevents classic betaAR desensitization-related signaling mechanisms at a molecular level. Therefore, via immunoblotting, radioligand binding, fluorescence resonance energy transfer (FRET) and microscopy assays, we have performed an assessment of the effect of paroxetine on proximal betaAR signaling responses. Indeed, paroxetine treatment inhibited ligand-induced beta2AR phosphorylation in a concentration-dependent manner. Additionally, for both beta1AR and beta2AR, paroxetine decreased ligand-induced betaarrestin2 recruitment and subsequent receptor internalization. Thus, paroxetine inhibits betaAR desensitization mechanisms consistent with GRK2 inhibition and provides a useful pharmacological tool for studying these proximal GPCR signaling responses.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Paroxetine	Beta adrenergic receptor (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details