Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes
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A key question in receptor signaling is how specificity is realized, particularly when different receptors trigger the same biochemical pathway(s). A notable case is the two β-adrenergic receptor (β-AR) subtypes, β1 and β2, in cardiomyocytes. They are both coupled to stimulatory Gs proteins, mediate an increase in cyclic adenosine monophosphate (cAMP), and stimulate cardiac contractility; however, other effects, such as changes in gene transcription leading to cardiac hypertrophy, are prominent only for β1-AR but not for β2-AR. Here, we employ highly sensitive fluorescence spectroscopy approaches, in combination with a fluorescent β-AR antagonist, to determine the presence and dynamics of the endogenous receptors on the outer plasma membrane as well as on the T-tubular network of intact adult cardiomyocytes. These techniques allow us to visualize that the β2-AR is confined to and diffuses within the T-tubular network, as opposed to the β1-AR, which is found to diffuse both on the outer plasma membrane as well as on the T-tubules. Upon overexpression of the β2-AR, this compartmentalization is lost, and the receptors are also seen on the cell surface. Such receptor segregation depends on the development of the T-tubular network in adult cardiomyocytes since both the cardiomyoblast cell line H9c2 and the cardiomyocyte-differentiated human-induced pluripotent stem cells express the β2-AR on the outer plasma membrane. These data support the notion that specific cell surface targeting of receptor subtypes can be the basis for distinct signaling and functional effects.
Bathe-Peters , M , Gmach , P , Boltz , H H , Einsiedel , J , Gotthardt , M , Hübner , H , Gmeiner , P , Lohse , M J & Annibale , P 2021 , ' Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 118 , no. 23 , e2101119118 . https://doi.org/10.1073/PNAS.2101119118
Proceedings of the National Academy of Sciences of the United States of America
Copyright © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
DescriptionAuthors acknowledge funding from Deutsche Forschungs-gemeinschaft (DFG; German Research Foundation) collaborative research center 1423 Project 421152132, Subproject C03 (to M.J.L. and P.A.) and DFG Cluster of Excellence EXC2046 Math+ (to M.J.L. and P.A.). We acknowledge Narasimha Telugu from the Max Delbrück Center stem cell core facility for guidance and advice with the culture and differentiation of hiPSCs and Marlies Grieben for technical assistance.
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