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The role of CaMKII regulation of phospholamban activity in heart disease

Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca(2)(+)-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser(16) by PKA or Thr(17) by Ca(2)(+)-calmodulin...

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Autores principales: Mattiazzi, Alicia, Kranias, Evangelia G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913884/
https://www.ncbi.nlm.nih.gov/pubmed/24550830
http://dx.doi.org/10.3389/fphar.2014.00005
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author Mattiazzi, Alicia
Kranias, Evangelia G.
author_facet Mattiazzi, Alicia
Kranias, Evangelia G.
author_sort Mattiazzi, Alicia
collection PubMed
description Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca(2)(+)-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser(16) by PKA or Thr(17) by Ca(2)(+)-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca(2)(+) uptake, Ca(2)(+) load, contractility, and relaxation. PLN phosphorylation is also the main determinant of β1-adrenergic responses in the heart. Although phosphorylation of Thr(17) by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca(2)(+), necessary to activate CaMKII. Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1. Regulation of PLN activity by this multimeric complex becomes even more important in pathological conditions, characterized by aberrant Ca(2)(+)-cycling. In this scenario, CaMKII-dependent PLN phosphorylation has been associated with protective effects in both acidosis and ischemia/reperfusion. However, the beneficial effects of increasing SR Ca(2)(+) uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca(2)(+) leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca(2)(+) uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca(2)(+) load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca(2)(+) uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr(17) on cardiac function under physiological and pathological conditions.
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spelling pubmed-39138842014-02-18 The role of CaMKII regulation of phospholamban activity in heart disease Mattiazzi, Alicia Kranias, Evangelia G. Front Pharmacol Pharmacology Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca(2)(+)-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser(16) by PKA or Thr(17) by Ca(2)(+)-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca(2)(+) uptake, Ca(2)(+) load, contractility, and relaxation. PLN phosphorylation is also the main determinant of β1-adrenergic responses in the heart. Although phosphorylation of Thr(17) by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca(2)(+), necessary to activate CaMKII. Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1. Regulation of PLN activity by this multimeric complex becomes even more important in pathological conditions, characterized by aberrant Ca(2)(+)-cycling. In this scenario, CaMKII-dependent PLN phosphorylation has been associated with protective effects in both acidosis and ischemia/reperfusion. However, the beneficial effects of increasing SR Ca(2)(+) uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca(2)(+) leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca(2)(+) uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca(2)(+) load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca(2)(+) uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr(17) on cardiac function under physiological and pathological conditions. Frontiers Media S.A. 2014-01-27 /pmc/articles/PMC3913884/ /pubmed/24550830 http://dx.doi.org/10.3389/fphar.2014.00005 Text en Copyright © 2014 Mattiazzi and Kranias. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Mattiazzi, Alicia
Kranias, Evangelia G.
The role of CaMKII regulation of phospholamban activity in heart disease
title The role of CaMKII regulation of phospholamban activity in heart disease
title_full The role of CaMKII regulation of phospholamban activity in heart disease
title_fullStr The role of CaMKII regulation of phospholamban activity in heart disease
title_full_unstemmed The role of CaMKII regulation of phospholamban activity in heart disease
title_short The role of CaMKII regulation of phospholamban activity in heart disease
title_sort role of camkii regulation of phospholamban activity in heart disease
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913884/
https://www.ncbi.nlm.nih.gov/pubmed/24550830
http://dx.doi.org/10.3389/fphar.2014.00005
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