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Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts
Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β(2)-adrenoceptor (β(2)AR) stimulation, which may underlie the development of Takotsubo cardiomyopathy. However, both cell types produce comparable cytosolic amounts of the second messenger cAMP. W...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912947/ https://www.ncbi.nlm.nih.gov/pubmed/29642004 http://dx.doi.org/10.1016/j.celrep.2018.03.053 |
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author | Wright, Peter T. Bhogal, Navneet K. Diakonov, Ivan Pannell, Laura M.K. Perera, Ruwan K. Bork, Nadja I. Schobesberger, Sophie Lucarelli, Carla Faggian, Giuseppe Alvarez-Laviada, Anita Zaccolo, Manuela Kamp, Timothy J. Balijepalli, Ravi C. Lyon, Alexander R. Harding, Sian E. Nikolaev, Viacheslav O. Gorelik, Julia |
author_facet | Wright, Peter T. Bhogal, Navneet K. Diakonov, Ivan Pannell, Laura M.K. Perera, Ruwan K. Bork, Nadja I. Schobesberger, Sophie Lucarelli, Carla Faggian, Giuseppe Alvarez-Laviada, Anita Zaccolo, Manuela Kamp, Timothy J. Balijepalli, Ravi C. Lyon, Alexander R. Harding, Sian E. Nikolaev, Viacheslav O. Gorelik, Julia |
author_sort | Wright, Peter T. |
collection | PubMed |
description | Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β(2)-adrenoceptor (β(2)AR) 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 β(2)AR/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 β(2)AR. 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. |
format | Online Article Text |
id | pubmed-5912947 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-59129472018-04-27 Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts Wright, Peter T. Bhogal, Navneet K. Diakonov, Ivan Pannell, Laura M.K. Perera, Ruwan K. Bork, Nadja I. Schobesberger, Sophie Lucarelli, Carla Faggian, Giuseppe Alvarez-Laviada, Anita Zaccolo, Manuela Kamp, Timothy J. Balijepalli, Ravi C. Lyon, Alexander R. Harding, Sian E. Nikolaev, Viacheslav O. Gorelik, Julia Cell Rep Article Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β(2)-adrenoceptor (β(2)AR) 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 β(2)AR/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 β(2)AR. 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. Cell Press 2018-04-10 /pmc/articles/PMC5912947/ /pubmed/29642004 http://dx.doi.org/10.1016/j.celrep.2018.03.053 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wright, Peter T. Bhogal, Navneet K. Diakonov, Ivan Pannell, Laura M.K. Perera, Ruwan K. Bork, Nadja I. Schobesberger, Sophie Lucarelli, Carla Faggian, Giuseppe Alvarez-Laviada, Anita Zaccolo, Manuela Kamp, Timothy J. Balijepalli, Ravi C. Lyon, Alexander R. Harding, Sian E. Nikolaev, Viacheslav O. Gorelik, Julia Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts |
title | Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts |
title_full | Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts |
title_fullStr | Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts |
title_full_unstemmed | Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts |
title_short | Cardiomyocyte Membrane Structure and cAMP Compartmentation Produce Anatomical Variation in β(2)AR-cAMP Responsiveness in Murine Hearts |
title_sort | cardiomyocyte membrane structure and camp compartmentation produce anatomical variation in β(2)ar-camp responsiveness in murine hearts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912947/ https://www.ncbi.nlm.nih.gov/pubmed/29642004 http://dx.doi.org/10.1016/j.celrep.2018.03.053 |
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