Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4

The EMBO Journal
Wito RichterM Conti

Abstract

Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that beta1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a beta2AR/beta-arrestin/PDE complex reported previously. The beta1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the beta2AR is a prerequisite for the recruitment of a complex consisting of beta-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of beta1- and beta2-adrenoceptor signaling.

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Citations

Dec 17, 2010·Basic Research in Cardiology·Wito RichterMarco Conti
May 20, 2011·Current Heart Failure Reports·Magali BerthouzeFrank Lezoualc'h
Jul 25, 2009·Current Treatment Options in Cardiovascular Medicine·Giuseppe RengoWalter J Koch
Apr 3, 2012·Biologie aujourd'hui·Delphine MikaRodolphe Fischmeister
Apr 12, 2012·Proceedings of the National Academy of Sciences of the United States of America·Shubai LiuYang K Xiang
Apr 18, 2009·The Journal of Biological Chemistry·Xiang LiMiles D Houslay
Oct 6, 2009·The Journal of Biological Chemistry·Vania De ArcangelisYang Xiang
Apr 6, 2011·The Journal of Biological Chemistry·David M ZuckermanCarolyn E Machamer
May 30, 2008·The Journal of Biological Chemistry·Matthew D BrussMarco Conti
Feb 17, 2009·The Journal of Biological Chemistry·Cecile TerrenoireRobert S Kass
Jan 1, 2014·The Journal of General Physiology·Marco ContiWito Richter
Apr 30, 2010·Pharmacological Reviews·Louis M Luttrell, Diane Gesty-Palmer
Jul 9, 2011·Circulation Research·Yang K Xiang
Aug 30, 2013·Cell Communication and Signaling : CCS·Norma C SalazarAnastasios Lymperopoulos
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Jul 26, 2013·Expert Opinion on Therapeutic Targets·Wito RichterMarco Conti
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Feb 6, 2013·EMBO Reports·Wito RichterMarco Conti
Nov 28, 2009·The EMBO Journal·Mei-ling A JoinerJohannes W Hell
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Jun 9, 2012·Journal of the American College of Cardiology·Cristina E MolinaRodolphe Fischmeister
Jan 26, 2016·Cellular Signalling·Lauren WillsGeorge S Baillie
Nov 5, 2016·Biologie aujourd'hui·Ibrahim BediouneGrégoire Vandecasteele
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May 18, 2016·Archives of Cardiovascular Diseases·Pierre BobinGrégoire Vandecasteele
Apr 24, 2014·Pflügers Archiv : European journal of physiology·Aziz GuellichRodolphe Fischmeister

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Methods Mentioned

BETA
immunoprecipitation
pull-down
co-IP

Software Mentioned

DATAQ
Windaq waveform Browser
GraphPad Prism
ScionImage

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