Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Altered intracellular Ca2+ handling in heart failure
Masafumi Yano, … , Yasuhiro Ikeda, Masunori Matsuzaki
Masafumi Yano, … , Yasuhiro Ikeda, Masunori Matsuzaki
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):556-564. https://doi.org/10.1172/JCI24159.
View: Text | PDF
Review Series

Altered intracellular Ca2+ handling in heart failure

  • Text
  • PDF
Abstract

Structural and functional alterations in the Ca2+ regulatory proteins present in the sarcoplasmic reticulum have recently been shown to be strongly involved in the pathogenesis of heart failure. Chronic activation of the sympathetic nervous system or of the renin-angiotensin system induces abnormalities in both the function and structure of these proteins. We review here the considerable body of evidence that has accumulated to support the notion that such abnormalities contribute to a defectiveness of contractile performance and hence to the progression of heart failure.

Authors

Masafumi Yano, Yasuhiro Ikeda, Masunori Matsuzaki

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Intracellular Ca2+ cycling and associated signaling pathway in cardiomyo...
Intracellular Ca2+ cycling and associated signaling pathway in cardiomyocytes. On a beat-by-beat basis, a calcium transient is evoked by the initial influx of a small amount of Ca2+ through the LTCC and the subsequent large-scale Ca2+ release from the SR through the RyR. During diastole, cytosolic Ca2+ is taken up into the SR by the PLN-regulated SERCA2a pump. β receptor–mediated PKA stimulation regulates this Ca2+ cycling by phosphorylating LTCC, RyR, and PLN. In normal hearts, sympathetic stimulation activates β1-adrenergic receptor, which in turn stimulates the production of cAMP by adenylyl cyclase and thereby activates PKA. PKA phosphorylates PLN and RyR, both of which contribute to an increased intracellular Ca2+ transient and enhanced cellular contractility (pink zone signal). PP1 and PP2A regulate the dephosphorylation process of these Ca2+ regulatory proteins (RyR, PLN, LTCC) (blue zone signaling). Activation of the Gαq-coupled receptors (angiotensin II receptor, endothelin 1 receptor, or α-adrenergic receptor) activates PLC, which in turn activates PKC-α. The PKC-α phosphorylates I-1, augmenting the activity of PP1 and causing hypophosphorylation of PLB. The PLB hypophosphorylation inhibits SERCA2a activity, thereby decreasing SR Ca2+ uptake. The increased Ca2+ level in the cytosol activates CAMKII, which affects the functions of RyR and PLN. Activation or deactivation of these molecules at a node in the signaling cascade affects beat-by-beat Ca2+ cycling, and such maneuvers have recently been highlighted as potential new therapeutic strategies against HF. α, G protein subunit α; β, G protein subunit β; γ, G protein subunit γ; AC, adenylyl cyclase; PLC, phospholipase C.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts