Cardiomyocyte membrane structure and cAMP compartmentation produce anatomical variation in β2AR-cAMP responsiveness in murine hearts

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Title: Cardiomyocyte membrane structure and cAMP compartmentation produce anatomical variation in β2AR-cAMP responsiveness in murine hearts
Author(s): Wright, PT
Bhogal, N
Diakonov, I
Pannell, L
Perera, R
Bork, N
Schobesberger, S
Lucarelli, C
Faggian, G
Alvarez-Laviada, A
Zaccolo, M
Kamp, TJ
Balijepalli, R
Lyon, A
Harding, SE
Nikolaev, V
Gorelik, J
Item Type: Journal Article
Abstract: Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β2-adrenoceptor (β2AR) stimulation, which may underlie the development of Takotsubo cardiomyopathy. However, both cell types produce comparable cytosolic amounts of the second messenger cAMP. We investigated this discrepancy using nanoscale imaging techniques and found that, structurally, basal cardiomyocytes have more organized membranes (higher T-tubular and caveolar densities). Local membrane microdomain responses measured in isolated basal cardiomyocytes or in whole hearts revealed significantly smaller and more short-lived β2AR/cAMP signals. Inhibition of PDE4, caveolar disruption by removing cholesterol or genetic deletion of Cav3 eliminated differences in local cAMP production and equilibrated the contractile response to β2AR. We conclude that basal cells possess tighter control of cAMP because of a higher degree of signaling microdomain organization. This provides varying levels of nanostructural control for cAMP-mediated functional effects that orchestrate macroscopic, regional physiological differences within the heart.
Publication Date: 10-Apr-2018
Date of Acceptance: 14-Mar-2018
URI: http://hdl.handle.net/10044/1/58048
DOI: https://dx.doi.org/10.1016/j.celrep.2018.03.053
ISSN: 2211-1247
Publisher: Elsevier
Start Page: 459
End Page: 469
Journal / Book Title: Cell Reports
Volume: 23
Issue: 2
Sponsor/Funder: British Heart Foundation
Medical Research Council (MRC)
British Heart Foundation
Funder's Grant Number: FS/11/67/28954
MR/L006855/1
RG/17/13/33173
Copyright Statement: © 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
STRESS-INDUCED CARDIOMYOPATHY
ADULT CARDIAC MYOCYTES
PROTEIN-KINASE
VENTRICULAR MYOCARDIUM
SIGNALING COMPARTMENTS
MODEL REVEALS
CYCLIC-AMP
RAT
CAVEOLAE
CANINE
T-tubules
cAMP
cardiomyocytes
caveolae
microdomains
β(2) adrenoceptor
Publication Status: Published
Online Publication Date: 2018-04-10
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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