Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Bathe-Peters, Marc; Gmach, Philipp; Boltz, Horst-Holger; Einsiedel, Jürgen; Gotthardt, Michael; Hübner, Harald; Gmeiner, Peter; Annibale, Paolo

doi:10.1073/pnas.2101119118

Cited by 34 publications

(48 citation statements)

References 58 publications

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“…This work demonstrates that, in overexpression systems, βAR loses their normal localization and kinetics, becoming more motile within the cell membrane. Intriguingly, this paper also mentions populations of cells in which β1AR are absent, which is consistent with mosaicism with respect to muscarinic receptors as well [ 118 ].…”

Section: Experimental Techniques To Probe Tat/βar Effects In Cardiomyocytes With ‘Tubular’ Resolutionsupporting

confidence: 80%

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

Gorelik

Harding

2021

Cells

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Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.

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Section: Experimental Techniques To Probe Tat/βar Effects In Cardiomyocytes With ‘Tubular’ Resolutionsupporting

confidence: 80%

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

Gorelik

Harding

2021

Cells

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“…In a classic view, the βARs signal from the PM, including T-tubular and crest membrane. While the β 1 ARs are found on the entire cell surface, the β 2 ARs are exclusively targeted to the T-tubules [ 3 ]. The T-tubular membrane forms dyads together with the juxtamembrane of the SR, allowing tight coupling between LTCC and RyR2 and increasing [Ca 2+ ]i during E–C coupling.…”

Section: Discussionmentioning

confidence: 99%

Monoamine oxidase A and organic cation transporter 3 coordinate intracellular β1AR signaling to calibrate cardiac contractile function

Wang

Zhao

et al. 2022

Basic Res Cardiol

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We have recently identified a pool of intracellular β1 adrenergic receptors (β1ARs) at the sarcoplasmic reticulum (SR) crucial for cardiac function. Here, we aim to characterize the integrative control of intracellular catecholamine for subcellular β1AR signaling and cardiac function. Using anchored Förster resonance energy transfer (FRET) biosensors and transgenic mice, we determined the regulation of compartmentalized β1AR-PKA signaling at the SR and plasma membrane (PM) microdomains by organic cation transporter 3 (OCT3) and monoamine oxidase A (MAO-A), two critical modulators of catecholamine uptake and homeostasis. Additionally, we examined local PKA substrate phosphorylation and excitation–contraction coupling in cardiomyocyte. Cardiac-specific deletion of MAO-A (MAO-A-CKO) elevates catecholamines and cAMP levels in the myocardium, baseline cardiac function, and adrenergic responses. Both MAO-A deletion and inhibitor (MAOi) selectively enhance the local β1AR-PKA activity at the SR but not PM, and augment phosphorylation of phospholamban, Ca2+ cycling, and myocyte contractile response. Overexpression of MAO-A suppresses the SR-β1AR-PKA activity and PKA phosphorylation. However, deletion or inhibition of OCT3 by corticosterone prevents the effects induced by MAOi and MAO-A deletion in cardiomyocytes. Deletion or inhibition of OCT3 also negates the effects of MAOi and MAO-A deficiency in cardiac function and adrenergic responses in vivo. Our data show that MAO-A and OCT3 act in concert to fine-tune the intracellular SR-β1AR-PKA signaling and cardiac fight-or-flight response. We reveal a drug contraindication between anti-inflammatory corticosterone and anti-depressant MAOi in modulating adrenergic regulation in the heart, providing novel perspectives of these drugs with cardiac implications.

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“…Despite this, there are some issues with the research on GPCR signaling in endomembranes. For example, the study of over-expressed receptors can lead to mis-localization, as with the β-adrenergic receptor 2 (β2-AR) [120]. Many GPCRs require interaction with specific molecular chaperones, including RAMP [121], MRAP [122] and REEP [123] for their correct localization to the plasma membrane.…”

Section: Gpcr Signaling: Conventional Plasma Membrane Vs Endomembrane...mentioning

confidence: 99%

Endomembrane-Based Signaling by GPCRs and G-Proteins

Liccardo

Luini

Martino

2022

Cells

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G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of specific transduction pathways. For many years, biologists thought that GPCR signaling occurred entirely on the plasma membrane. However, in recent decades, many lines of evidence have proved that the GPCRs and G-proteins may reside on endomembranes and can start or propagate signaling pathways through the organelles that form the secretory route. How these alternative intracellular signaling pathways of the GPCR and G-proteins influence the physiological and pathological function of the endomembranes is still under investigation. Here, we review the general role and classification of GPCRs and G-proteins with a focus on their signaling pathways in the membrane transport apparatus.

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Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Cited by 34 publications

References 58 publications

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

Monoamine oxidase A and organic cation transporter 3 coordinate intracellular β1AR signaling to calibrate cardiac contractile function

Endomembrane-Based Signaling by GPCRs and G-Proteins

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