Cardiomyocyte membrane structure and cAMP compartmentation produce anatomical variation in β2AR-cAMP responsiveness in murine hearts
File(s)
Published version
Author(s)
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.
Date Issued
2018-04-10
Date Acceptance
2018-03-14
Citation
Cell Reports, 2018, 23 (2), pp.459-469
ISSN
2211-1247
Publisher
Elsevier
Start Page
459
End Page
469
Journal / Book Title
Cell Reports
Volume
23
Issue
2
Copyright Statement
© 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor
British Heart Foundation
Medical Research Council (MRC)
British Heart Foundation
Grant Number
FS/11/67/28954
MR/L006855/1
RG/17/13/33173
Subjects
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
Date Publish Online
2018-04-10